Conditions: Hereditary Hemochromatosis
Keywords: hereditary hemochromatosis ICL670 deferasirox FCT iron overload
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 45
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of deferasirox film coated tablet (FCT) versus phlebotomy for the management of iron overload in adults with Hereditary Hemochromatosis (HH) at risk of iron-related morbidity. This evaluation provided information on the two treatment options in terms of the rate of response of proportion of patients reaching the study target SF ≤ 100 μg/L and their associated safety profiles.

In addition to exploring the safety and efficacy of deferasirox FCT in hereditary hemochromatosis (HH), this study is being conducted to fulfill an FDA post-marketing requirement \[PMC 750-10 (Exjade) /PMR 2888-8 (Jadenu)\] to provide additional randomized data to confirm the ocular safety profile of deferasirox through detailed ocular assessments in patients treated with deferasirox FCT for 2 years.

Detailed description:
This was a Phase II, multicenter, open-label, randomized two-year study in adults with Hereditary Hemochromatosis (HH) confirmed by HH genotype with iron overload. Eligible subjects were identified during a 4-week screening period, then randomized in a 2:1 ratio to be treated with deferasirox FCT or phlebotomy for up to 24 months (104 weeks).

Arms:
arm 1: An initial dose of deferasirox FCT 7 mg/kg/day was used for 3 months (12 weeks), then was adjusted according to the serum ferritin (SF) level. Deferasirox was interrupted when the study-defined target SF ≤ 100 μg/L was achieved. Deferasirox was to be reinitiated when SF ≥ 300 μg/L, according to deferasirox label. arm 2: Phlebotomy was conducted at a frequency determined by the physician. Phlebotomy was interrupted when the study-defined target SF ≤ 100 μg/L was achieved. Phlebotomy was to be reinitiated when SF \> 100 μg/L, based on standard of care practice.

Interventions: intervention 1: Deferasirox FCT intervention 2: Phlebotomy
Intervention descriptions: intervention 1: Taken orally once per day (QD) as a film coated tablet (FCT) intervention 2: according to investigator's decision

Protocol document:
Prot_000.pdf: 
Clinical Development
ICL670, Deferasirox
Clinical Protocol CICL670F2203 / NCT03203850
A phase II, multicenter, open-label, randomized two-year 
study to evaluate the efficacy and safety of deferasirox 
film-coated tablet versus phlebotomy in patients with 
Hereditary Hemochromatosis
Document type
Amended Protocol Version
EUDRACT number
2016-002529-12
Version number
01 (Global Amended Protocol Version) Clean
Development phase
II
Document status
Final
Release date
30-Aug-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 15-Jan-2017


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary:.............................................................................................................10
Global Amendment 01 (30-Aug-2018) .............................................................................15
1
Background........................................................................................................................19
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............19
1.2
Introduction to investigational treatment(s) and other study treatment(s).............19
1.2.1
Overview of deferasirox........................................................................19
2
Rationale............................................................................................................................20
2.1
Study rationale and purpose...................................................................................20
2.2
Rationale for the study design ...............................................................................21
2.3
Rationale for dose and regimen selection..............................................................21
2.4
Rationale for choice of combination drugs............................................................21
2.5
Rationale for choice of comparators drugs............................................................21
2.6
Risks and benefits..................................................................................................22
3
Objectives and endpoints...................................................................................................23
4
Study design ......................................................................................................................25
4.1
Description of study design ...................................................................................25
4.1.1
Post-treatment Ocular Follow-up..........................................................25
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


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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................................................................................31
6.2
Dose escalation guidelines.....................................................................................31
6.3
Dose modifications................................................................................................31
6.3.1
Dose modification and dose delay ........................................................31
6.3.2
Dose adjustments for QTcF prolongation.............................................37
6.3.3
Follow-up for toxicities.........................................................................37
6.4
Concomitant medications ......................................................................................38
6.4.1
Permitted concomitant therapy .............................................................38
6.4.2
Permitted concomitant therapy requiring caution and/or action...........38
6.4.3
Prohibited concomitant therapy ............................................................39
6.4.4
Use of Bisphosphonates ........................................................................39
6.5
Patient numbering, treatment assignment or randomization .................................39
6.5.1
Patient numbering .................................................................................39
6.5.2
Treatment assignment or randomization...............................................39
6.5.3
Treatment blinding................................................................................40
6.6
Study drug preparation and dispensation...............................................................40
6.6.1
Study treatment packaging and labeling ...............................................40
6.6.2
Drug supply and storage........................................................................41
6.6.3
Study drug compliance and accountability ...........................................41
6.6.4
Disposal and destruction .......................................................................41
7
Visit schedule and assessments .........................................................................................42
7.1
Study flow and visit schedule................................................................................42
7.1.1
Molecular pre-screening........................................................................48
7.1.2
Screening...............................................................................................48
7.1.3
Run-in period ........................................................................................49
7.1.4
Treatment period...................................................................................49
7.1.5
Discontinuation of study treatment .......................................................50
7.1.6
Withdrawal of consent ..........................................................................50
7.1.7
Follow up for safety evaluations...........................................................51
7.1.8
Lost to follow-up...................................................................................51


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7.2
Assessment types...................................................................................................51
7.2.1
Efficacy assessments.............................................................................51
7.2.2
Safety and tolerability assessments.......................................................52
7.2.3
Pharmacokinetics ..................................................................................57
7.2.4
Biomarkers............................................................................................57
7.2.5
Resource utilization...............................................................................57
7.2.6
Patient reported outcomes.....................................................................57
8
Safety monitoring and reporting........................................................................................57
8.1
Adverse events (AEs) ............................................................................................57
8.1.1
Definitions and reporting ......................................................................57
8.1.2
Laboratory test abnormalities................................................................58
8.1.3
Adverse events of special interest.........................................................59
8.2
Serious adverse events...........................................................................................59
8.2.1
Definitions.............................................................................................59
8.2.2
Reporting...............................................................................................60
8.3
Emergency unblinding of treatment assignment ...................................................60
8.4
Pregnancies............................................................................................................61
8.5
Warnings and precautions......................................................................................61
8.6
Data Monitoring Committee..................................................................................61
8.7
Steering Committee ...............................................................................................61
9
Data collection and management.......................................................................................62
9.1
Data confidentiality ...............................................................................................62
9.2
Site monitoring ......................................................................................................62
9.3
Data collection.......................................................................................................63
9.4
Database management and quality control............................................................63
10 Statistical methods and data analysis ................................................................................64
10.1
Analysis sets ..........................................................................................................64
10.1.1
Full Analysis Set ...................................................................................64
10.1.2
Safety set ...............................................................................................64
10.1.3
Per Protocol Analysis Set:.....................................................................64
10.1.4
Pharmacokinetic analysis set.................................................................64
10.1.5
Other analysis sets.................................................................................64
10.2
Patient demographics/other baseline characteristics .............................................65


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10.3
Treatments (study treatment, concomitant therapies, compliance) .......................65
10.4
Primary objective...................................................................................................65
10.4.1
Variable.................................................................................................65
10.4.2
Statistical hypothesis, model, and method of analysis..........................66
10.4.3
Handling of missing values/censoring/discontinuations.......................66
10.4.4
Supportive and Sensitivity analyses......................................................66
10.5
Secondary objectives .............................................................................................66
10.5.1
Key secondary objective .......................................................................66
10.5.2
Secondary efficacy objective(s)............................................................66
10.5.3
Secondary safety objectives..................................................................67
10.5.4
Pharmacokinetics ..................................................................................69
10.5.5
Biomarkers............................................................................................69
10.5.6
Resource utilization...............................................................................70
10.5.7
Patient-reported outcomes.....................................................................70
10.6
Exploratory objectives...........................................................................................70
10.7
Interim analysis......................................................................................................70
10.8
Sample size calculation..........................................................................................70
10.9
Power for analysis of key secondary variables......................................................71
11 Ethical considerations and administrative procedures ......................................................71
11.1
Regulatory and ethical compliance........................................................................71
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................71
11.3
Informed consent procedures.................................................................................71
11.4
Discontinuation of the study..................................................................................72
11.5
Publication of study protocol and results...............................................................72
11.6
Study documentation, record keeping and retention of documents.......................72
11.7
Confidentiality of study documents and patient records .......................................73
11.8
Audits and inspections...........................................................................................73
11.9
Financial disclosures..............................................................................................73
12 Protocol adherence ............................................................................................................74
12.1
Amendments to the protocol..................................................................................74
13 References (available upon request)..................................................................................75
14 Appendices ........................................................................................................................76
14.1
Dosing tables (Deferasirox FCT)...........................................................................76


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14.2
Examples of light meal ..........................................................................................78
List of figures
Figure 4-1
Study schema ........................................................................................25
List of tables
Table 3-1
Objectives and related endpoints ..........................................................24
Table 6-1
Dose and treatment schedule.................................................................29
Table 6-2
Criteria for dose reduction / interruption and re-initiation of 
deferasirox FCT ....................................................................................32
Table 6-3
Packaging and labeling .........................................................................40
Table 7-1
Visit evaluation schedule ......................................................................43
Table 7-2
Central imaging assessments collection plan........................................53
Table 7-3
Central Clinical laboratory parameters collection plan.........................54
Table 10-1
Criteria for clinically notable and extended notable laboratory 
ranges ....................................................................................................68
Table 10-2
Definition of notable ranges for vital signs and weight ........................69
Table 10-3
Half-width of 95% CI of response rates in deferasirox FCT and 
phlebotomy arms...................................................................................70
Table 14-1
Dosing table for 3.5 mg/kg/day of Deferasirox FCT............................76
Table 14-2
Dosing table for 7 mg/kg/day of Deferasirox FCT ...............................76
Table 14-3
Dosing table for 10.5 mg/kg/day of Deferasirox FCT..........................77
Table 14-4
Dosing table for 14 mg/kg/day of Deferasirox FCT.............................77


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List of abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
CDS
CI
Core data sheet
Confidence interval
CRA
EBV
Clinical Research Associate
Epstein-Barr virus
EDC
Electronic data capture
ETDRS
Early treatment diabetic retinopathy study
EOS
End of study
EOT
End of treatment
CMV
Cytomegalovirus
CRO
Contract research organization
CSR
Clinical study report
CMO&PS
Chief Medical Office and Patient Safety
DILI
Drug-induced liver injury
DT
Dispersible tablet
ECG
Electrocardiogram
eCRF
Electronic case report/record form
ELISA
Enzyme-linked immunosorbent assay
FAS
Full analysis set
FCT
Film-coated tablet
GCP
Good clinical practice
GGT
Gamma-glutamyl transferase
HFE
High iron Fe gene
HH
Hereditary hemochromatosis 
HSV
Herpes Simplex Virus
ICF
Informed consent form
ICH
International conference on harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICMJE
International committee of medical journal editors
IEC
Independent ethics committee
IN
Investigator notification
IOP
Intraocular pressure
IRB
Institutional review board
IRT
Interactive response technology


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LFT
Liver function test
LOCS
Lens Opacities Classification System
PI
Principal Investigator
PT
Preferred Term
SAP
Statistical analysis plan
SC
Steering committee
SF
Serum ferritin
SI
International system of units
SUSARs
Suspected unexpected serious adverse reactions
RR
Response rate
REB
Research ethics board
SAE
Serious adverse event
SJS
SmPC
Stevens-Johnson syndrome
Summary of product characterstic
SOC
System organ class
SOP
Standard operating procedure
ULN
Upper limit normal
UPCR
Urine protein/ creatinine ratio


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic samples
A biological specimen, including blood (plasma, serum), saliva, tissue,
urine, stool, taken from a study subject or study patient
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained, i.e., prior to starting any 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 properties 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 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 within their approved indication/dosage.
Medication number
A unique identifier on the label of each study treatment package which 
is linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Subject number
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information, and biological samples
Randomization number
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment
Statistical analysis plan
A regulatory document which provides evidence of preplanned 
analyses
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
Any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason
Treatment group
A treatment group defines the dose and regimen
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points
Withdrawal of consent
Withdrawal of study consent: Withdrawal of consent from the study 
occurs only when a subject does not want to participate in the study 
any longer, and does not allow any further collection of personal data


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Protocol summary: 
Title
A phase II, multicenter, open-label, randomized two-year study to evaluate 
the efficacy and safety of deferasirox film-coated tablet versus phlebotomy 
in patients with Hereditary Hemochromatosis (HH)
Brief title
Study to evaluate the efficacy and safety of deferasirox film-coated tablet 
versus phlebotomy in patients with HH
Sponsor and Clinical 
Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Iron overload due to HH typically manifests between the third and sixth 
decades of life and is more common in males.  If untreated, iron 
accumulates in the organs and causes tissue injury and dysfunction.  
Although phlebotomy is generally tolerated well and is very effective, it may 
not always be feasible due to inconvenient clinic visits and discomfort 
associated with the procedure; This is particularly disadvantageous for 
patients with serum ferritin (SF) > 1000 μg/L who require more 
phlebotomy. In addition, a small percentage of patients may be ineligible 
for phlebotomy due to reduced venous access, congestive heart failure, or 
anemia. Oral iron chelation therapy will provide another option for patients 
either unwilling or unable to undergo a regular phlebotomy regimen.
The purpose of this study is to evaluate the efficacy and safety of 
deferasirox FCT versus phlebotomy for the management of iron overload 
in adults with HH at risk of iron-related morbidity. This evaluation will 
provide information on the two treatment options in terms of the rate of 
response of proportion of patients reaching the study target SF ≤ 100 μg/L 
and their associated safety profiles.  
In addition to exploring the safety and efficacy of deferasirox FCT in 
hereditary hemochromatosis (HH), this study is being conducted to fulfill an 
FDA post-marketing requirement [PMC 750-10 (Exjade) /PMR 2888-8 
(Jadenu)] to provide additional randomized data to confirm the ocular 
safety profile of deferasirox through detailed ocular assessments in 
patients treated with deferasirox FCT for 2 years.
Primary Objective(s) 
and Key Secondary 
Objective
Primary Objective: Assess the response rate in the deferasirox FCT and 
phlebotomy treatment arms where response is defined by achieving target 
SF ≤ 100 μg/L on or before 24 months.
Key Secondary Objective: Characterize the ocular safety of deferasirox 
FCT and phlebotomy over 24 months.
Secondary Objectives

Evaluate the safety and tolerability of deferasirox FCT and phlebotomy 
over 24 months.

Assess the change from baseline in visual acuity, intra-ocular 
pressure, retina or/and optic nerve abnormalities, and lens 
abnormalities at months 6, 12, 18, and 24 of deferasirox FCT and 
phlebotomy.

Assess the safety and tolerability of deferasirox FCT in patients who 


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interrupt and re-initiate treatment due to SF ≤ 100 μg/L and ≥ 300 μg/L.

Assess the first time to response (defined as SF ≤ 100 μg/L) between 
the deferasirox and phlebotomy treatment groups.
Study design
This is a Phase II, multicenter, open-label, randomized two-year study in 
150 adults confirmed by homozygous C282Y genotype with iron overload. 
Eligible patients will be identified during a 4-week screening period, then 
randomized in a 2:1 ratio (100 patients to deferasirox FCT and 50 patients 
to phlebotomy), and treated for 24 months (104 weeks).  After end of 
treatment (EOT), there is a standard 30-day safety follow-up.
If a patient discontinues from treatment in either arm and has completed at 
least 6 months of assessments, they will be encouraged to continue in a 
Post-treatment Ocular Follow-up phase and undergo ocular exams every 6 
months as scheduled to receive a total of at least 5 ophthalmological 
examinations.
End of study (EOS) occurs after the last patient has completed last visit 
which includes a 30-day safety follow-up.  This last patient may have either 
completed 24 months (104 weeks) of treatment, or prematurely 
discontinued and completed ocular assessments. After completing the 
study or discontinuing from study treatment, patients will receive standard 
of care.
Population
Adult hereditary hemochromatosis patients with iron overload
Inclusion criteria

Written informed consent must be obtained prior to any screening 
procedures.

Male or female ≥18-years-old

Documented genotype testing confirming homozygous for the C282Y 
mutation (C282Y/C282Y)

Transferrin saturation ≥ 45% (at either screening visit)

SF ≥ 500 μg/L (at either screening visit)
Exclusion criteria
1.
Medical conditions that preclude inclusion:

Iron overload not due to HH

Condition which might significantly alter the absorption, 
distribution, metabolism or excretion of oral deferasirox

Systemic disease which prevents taking study treatment or any 
contraindication to phlebotomy

Inflammatory condition or immunological disease which may 
interfere with the SF interpretation, such as an active infection, 
collagen vascular disorders, irritable bowel  syndrome, lupus, or 
immune thrombocytopenia

Significantly impaired gastrointestinal function or disease that may 
significantly alter the absorption of oral deferasirox, e.g. ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, or small bowel resection. 

Psychiatric or addictive disorder which prevent giving informed 
consent or undergoing any of the treatment options or unwilling or 
unable to comply with the protocol

Uncontrolled or significant cardiac disease or symptomatic cardiac 


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arrhythmias, e.g., sustained ventricular tachycardia and clinically 
significant second or third degree AV block without a pacemaker. 

Illicit drug use and/or alcohol use, defined as an average alcohol 
consumption greater than one standard drink a day for women or 
two standard drinks a day for men within the 12 months prior to 
enrolment. A standard drink is generally considered to be 12 
ounces (or 355 ml) of beer, 5 ounces (or 148 ml) of wine, or 1.5
ounces (or 44 ml) of 80-proof distilled spirits

Cirrhosis, including Child-Pugh class A, B, and C, diagnosed by 
liver biopsy, elastography, radiologic exams, or clinical criteria.

Active hepatitis B or C (hepatitis B carrier will be allowed)

History of HIV seropositivity (ELISA or Western blot)

Malignancy of any organ system, treated or untreated, within the 
past 5 years whether or not there is evidence of local recurrence or 
metastases, except localized basal cell carcinoma of the skin. 
Hepatocellular carcinoma at any time is excluded.
2.
Prior iron chelation therapy, prohibited concomitant medications with 
deferasirox. 
3.
Abnormal laboratory values:

Significant anemia that contraindicates phlebotomy (males with 
hemoglobin <130g/L, females with hemoglobin <120g/L in both 
screening visit samples

Platelets ≤ 50 x 109/L in both screening visit samples

Urine protein/urine creatinine ratio > 1.0 mg/mg in both non-first 
void urine screening visit samples

Creatinine clearance ≤ 40 ml/min in both screening visit samples 

Serum creatinine > 1.5 x ULN in both screening visit samples 

ALT ≥ 5 x ULN in both screening visit samples

Total bilirubin > 1.5 x ULN in both screening visit samples
4.
Participation in an investigational study:

Observational registry study is allowable

Within 30 days prior to enrollment or within 5-half-lives of an 
investigational product, whichever is longer
5.
Pregnancy and contraception:

Pregnant or nursing (lactating) women

Women of child-bearing potential unless using appropriate 
methods of contraception 

Post-menopausal and not of childbearing potential if she has had 
12 months of natural (spontaneous) amenorrhea with an expected 
clinical profile.
Investigational and 
reference therapy
Investigational drug: ICL670 (deferasirox):

Drug formulation: film-coated tablet (FCT)

Control arm: phlebotomy
Efficacy assessments

Primary efficacy endpoint will be assessed by response rate where 
response is defined by achieving target SF ≤ 100 μg/L on or before 24 


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months. SF is measured at screening, baseline, week 2, and thereafter 
every 4 weeks until week 104 (24 months).

Secondary efficacy endpoint will be assessed by the time to first 
response of achieving SF ≤ 100 μg/L. 
Safety assessments

Key secondary safety endpoint will be ocular safety as measured by 
incidence of the treatment emergent adverse events. 

Ocular assessments, including visual acuity (ETDRS), slit lamp exam 
(with LOCS III), tonometry, and fundus examination and photography 
will be assessed every 6 months.  

Laboratory parameters at screening, baseline, week 2, 4, then every 4 
weeks until end of treatment (week 104):

Hematology, chemistry (including renal and hepatic 
parameters) and urinalysis

Coagulation, urine protein/creatinine ratio, transferrin 
saturation, and SF

Vital signs at screening, baseline, week 2, 4, then every 4 weeks until 
end of treatment (week 104)

ECG and audiometry test at screening, week 24, 52, 76 and 104 
Other assessments
Not applicable
Data analysis
Primary objective:
Assess the response rate (RR) of the deferasirox FCT and phlebotomy 
treatment arms where a response is defined by achieving target SF ≤ 100 
μg/L on or before month 24. The estimate of the RR and the corresponding 
95% CI will be provided for each arm. No formal hypothesis testing is 
planned in this study. Any patient who discontinues prematurely before 
meeting the criteria will be considered a non-responder.
Key secondary objective:
Evaluate ocular safety of deferasirox FCT and phlebotomy over 24 months 
by the incidence of treatment-emergent ocular AEs (new or worsening from 
baseline). It will be summarized categorically by system organ class and/or 
preferred term, overall and by severity, type of AE, and relation to study 
treatment. 
No hypothesis will be tested for this key secondary objective.
Secondary efficacy objective:

Time to first response 
Response is defined when serum ferritin is ≤ 100 μg/L. For the analysis of 
time to first serum ferritin ≤ 100 μg/L, the following censoring rule will be 
applied:

For patients who did not achieve a response, they will be censored at 
the earliest of the following dates:

Death or discontinuation date due to any reason, or

Last SF assessment.
Kaplan-Meier estimates will be presented. Median time to response (as 
well as 25th and 75th percentiles) will be presented along with 95% 
confidence intervals for the two arms. 


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Secondary safety objectives:

Safety and tolerability of deferasirox FCT and phlebotomy over 24 
months

Change from baseline in visual acuity (ETDRS), intra-ocular pressure, 
retina or/and optic nerve abnormalities, and lens abnormalities at 
months 6, 12, 18, and 24

Safety and tolerability of deferasirox FCT in patients who interrupt due 
to SF ≤ 100 μg/L and re-initiate therapy when SF > 300 μg/L
During the 24 months of the study, safety and tolerability between 
deferasirox FCT and phlebotomy will be assessed by the incidence of new 
or worsening AEs, abnormal and clinical significant laboratory values, and 
other abnormal safety findings. 
The change from baseline in visual acuity (ETDRS), intra-ocular pressure, 
retina or/and optic nerve abnormalities, and lens abnormalities will be 
summarized descriptively by treatment and by visit. 
Incidence of AEs in patients who interrupted deferasirox FCT due to SF ≤ 
100 μg/L and re–initiated therapy in when SF > 300 μg/L will be reported.
Key words
Hereditary Hemochromatosis (HH), deferasirox, chelation, iron overload, 
phlebotomy, ocular safety


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Global Amendment 01 (30-Aug-2018)
Amendment rationale
The purpose of this amendment is to modify the inclusion and exclusion criteria, to correct 
inconsistencies, typos, add some clarifications and to update withdrawal of consent language. 
Additionally, the local French amendment text is formally integrated in this global 
amendment. However, the French specific requirements remain valid for France only.
At the time of this amendment, 7 patients have been randomized and 2 patients failed 
screening, both of them had the baseline serum ferritin values between 500 - 700 μg/L. In 
addition, out of 14 patients in prescreen who failed due to inclusion criteria, 10 patients had 
baseline serum ferritin values between 500 ~700 μg/L.
The inclusion criteria for baseline serum ferritin will be changed from ≥ 700μg/L to ≥500μg/L, 
which could allow more patients with iron overload to become eligible for the study 
enrollment, while ensuring collection of long term patient safety data.
The rationale for baseline serum ferritin change is as following:
A Phase I/II dose escalation study in Hereditary Hemochromatosis (CICL670A2202), 
deferasirox dispersible tablet (DT) 10 to 15 mg/kg/day had an acceptable safety profile 
(Phatak 2010). In a one-year Phase 2 study in HH patients (CICL670EBR14T), deferasirox
DT 10±5 mg/kg/day was well tolerated and effective in reducing iron burden (Cancado 2015). 
The inclusion criteria for these studies was serum ferritin between ≥ 300μg/L and ≤1500μg/L 
and serum ferritin ≥ 500ug/L respectively. 
According to the guideline (EASL 2010, Bacon 2011), all patients with homozygous 
hereditary hemochromatosis and evidence of iron overload (i.e., transferrin saturation greater 
than or equal 45 percent and serum ferritin level greater than 300 ug /L in men and greater 
than 200 ug/L in women) should be treated, regardless of symptoms.. 
The total duration of treatment for each patient in this study is up to 24 months (104 weeks) in 
order to collect safety information with prolonged treatment. When SF reaches the study 
target ≤ 100 μg/L, deferasirox FCT must be interrupted. The patients with low baseline serum 
ferritin (300~500μg/L) are more likely to reach the 100 μg/L threshold sooner than 24 months 
and will not substantially contribute to long term safety. Therefore, only patients with baseline 
serum ferritin ≥ 500μg/L would be enrolled in the study.
Changes to the protocol
Cover page

Amended to, authoring team member deleted according to new Novartis standard
List of abbreviation

Amended to, updatet


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Protocol No. CICL670F2203
Glossary of terms

Amended to, added wording according to new Novartis standard about personal data and 
withdrawal of consent
Protocol summary

Amended to, reflects the changes in different sections which are described in detail below
Section 5.2, Inclusion criteria 

(was) Serum Ferritin ≥ 700 μg/L
Amended to:
Serum Ferritin ≥ 500 μg/L (at either screening visit): See Rationale above
Section 5.3 Exclusion criteria 

(was) Malignancy of any organ system, treated or untreated, within the past 5 years
whether or not there is evidence of local recurrence or metastases, except localized basal 
cell carcinoma of the skin or any history of hepatocellular carcinoma
Amended to:
Malignancy of any organ system, treated or untreated, within the past 5 years whether or 
not there is evidence of local recurrence or metastases, except localized basal cell 
carcinoma of the skin. Hepatocellular carcinoma at any time is excluded.
Rationale: clarification about hepatocellular carcinoma and study participation

(was) Significant anemia that contraindicates phlebotomy (males with hemoglobin < 13 
mg/dL, females with hemoglobin < 12 mg/dL) in both screening visit samples
Amended to:
Significant anemia that contraindicates phlebotomy (males with hemoglobin < 130g/L, 
females with hemoglobin < 120g/L) in both screening visit samples ,
Rationale: correction of values for hemoglobin and changing to SI units (International 
system of units)

(was) Treatment with a systemic investigational drug within 4 weeks or topical invest-
gational drug within 7 days of starting the study
Amended to, deleted:
Rationale: deleted bullet point was contradictive to preceding bullet point, additionally 
even topical drugs can have long elimination half lives

(was) Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless using basic methods of contraception, 
Amended to, added: 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless using appropriate methods of contraception. Deferasirox may 
reduce the efficacy of hormonal contraception, thus it is recommended to use alternative 
methods of contraception.


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See Section 8.4 for pregnancy reporting and follow-up requirements,.
Rationale: clarification
Table 6.2 Criteria for dose reduction / interruption and re-initiation of deferasirox FCT 

(was) Determine lactose intolerance
Amended to, deleted, 
Rationale: the used deferasirox formulation no longer contains lactose

Amended to, added: 
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Rationale: according to update in actual CDS (core data sheet) and SmPC (Summary of 
Product Characteristics). 
Table 7.1 Visit evaluation schedule 

Amended to, added 
hematology and coagulation assessment at screening visit -2 weeks 
Rationale: alignment between text in protocol and table
Section 7.1.6, Withdrawal of Consent, 

Amended to, text revised:
Rationale: reflecting the new Novartis global consent withdrawal language
Section 7.2.2.6.6 Coagulation

(was) will be measured at the first screening visit
Amended to, added coagulation measurement for both screening visits
Rationale: alignment with assessments for hematology
Section 10.4.2 Statistical hypothesis, model, and method of analysis

(was)  = 	1 +

∗(
;,())

, 	1 +

()∗(
;(),())


Where x is the number of responders, n is the number of patients, α = the level of 
significance. The primary analysis will be carried out in the FAS. 
Amended to, deleted, 
Rationale; used Clopper-Pearson method is a well established method and needs no 
further explanation
Section Table 10-1 Criteria for clinically notable and extended notable laboratory ranges

Was: Hemoglobin  < 10 gm/dL
Amended to, Hemoglobin  < 100 g/L
Rationale: convert to L as reference volume


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Previous amendments
French local amendment
Amendment rationale 
 
to implement weekly monitoring of creatinine 
and creatinine clearance during “the first month after treatment initiation and when the dose is 
increased”
This affects sections 7.1, 7.1.4, and 7.2.2.6.3:  added assessments of creatinine and creatinine 
clearance at Week 1 and Week 3 after start of treatment. Weekly checks of creatinine and 
creatinine clearance during the first month after a dose increase is required for patients 
enrolled in sites from France only and should be regarded as unscheduled visits. 
IRB/IEC Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Hereditary Hemochromatosis (HH) is an inherited disorder characterized by life-long 
increased absorption of iron from the gastrointestinal tract. Over time, the accumulated excess 
iron is deposited in multiple organs and potentially leads to end-organ damage, especially in 
the liver, heart, pancreas, and endocrine organs.
Type 1 HH is one of the most common genetic disorders among Caucasians and has a 
prevalence of 1:200-1:400. The most common (80-90%) mutation of this autosomal recessive 
disorder is a homozygous mutation of the High Iron Fe (HFE) gene which results in a change 
of cysteine at position 282 to tyrosine (C282Y mutation).  The rest are either a change of 
histidine at position 63 to aspartate (H63D mutation) or compound heterozygotes with a 
single mutation in both the C282Y and H63D genes. Due to variable penetrance, many with 2 
copies of the C282Y mutation show no clinical significance. Only 25% of homozygous 
individuals develop a clinical problem, indicating that there are other genetic or 
environmental influences (Hanson 2001).
Therapeutic phlebotomy is the standard of care treatment for iron overload in HH (Bacon 
2011). Regular phlebotomy, such as weekly or biweekly, is done until iron stores normalize, 
followed by lifelong periodic phlebotomy therapy (often at quarterly intervals) based on iron 
re-accumulation.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of deferasirox
Deferasirox (company research code: ICL670; trade name: Exjade®, JadenuTM) is an orally 
active iron chelator that binds iron with high affinity and promotes excretion of excess iron, 
primarily in the feces.
1.2.1.1
Non-clinical experience
In vitro and in vivo studies demonstrated the high potency of deferasirox in mobilizing tissue 
iron and promoting iron excretion, and deferasirox was eliminated from the body by hepatic 
glucuronidation and biliary excretion. Preclinical studies demonstrated that deferasirox did 
not affect fertility and is neither teratogenic nor carcinogenic. Based on non-clinical studies, 
use in humans includes restricted in pregnancy and breast feeding and requires renal function 
monitoring and periodic ocular testing. Detailed preclinical information on deferasirox is in 
the current Investigators’ Brochure.


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1.2.1.2
Clinical experience
Deferasirox was approved for the treatment of chronic iron overload due to frequent blood 
transfusions (aged 2 years and older in more than 100 countries) and non-transfusion-
dependent thalassemia (aged 10 years and older in more than 70 countries). It is available as 
dispersible tablets (DT, trade name: Exjade®) and film-coated tablets [(FCT), tradename: 
JadenuTM in the US (United States), Canada, and some other countries; and as Exjade in EU
(European Union))].
Since approval on 2 November 2005, the dose-dependent efficacy of chelation therapy has 
been demonstrated for deferasirox DT in several large clinical trials with over 8121 patients 
exposed for up to 5 years and 
 The safety profile of 
deferasirox has been well characterized with the dispersible tablet formulation.
Because of the chronic nature of chelation therapy and the importance of patient compliance, 
an improved deferasirox formulation for oral administration was developed.  FCT contains the 
same active substance, but was strength-adjusted to achieve comparable exposure to the 
dispersible tablet. It is available in three dose strengths (90 mg, 180 mg and 360 mg) and is 
dosed based on weight. It can be taken with or without a light meal (See Appendix 14.2 for 
examples). The currently available clinical trial data with the FCT formulation suggests a 
safety and efficacy profile that is consistent with the known profile of the DT deferasirox 
formulation.
2
Rationale
2.1
Study rationale and purpose
Iron overload due to HH typically manifests between the third and sixth decades of life and is 
more common in males.  If untreated, iron accumulates in the organs and causes tissue injury 
and dysfunction.  Therefore, these patients might benefit from an iron chelator. If untreated in 
the liver, iron deposition will cause fibrosis, which may ultimately progress to cirrhosis and 
increased susceptibility to hepatocellular carcinoma. (Bacon 2011, Beaton and Adams 2007).  
Effects on the liver are exacerbated in alcoholics and in patients with chronic hepatitis B or C. 
Other manifestations include arthropathy, endocrinopathies (hypogonadism, sexual 
dysfunction, pancreatitis, or diabetes), and rarely, cardiomyopathy/cardiac failure with 
mortality (Niederau 1996, Morrison 2003).
Although phlebotomy is generally tolerated well and is very effective, it may not always be 
feasible due to inconvenient clinic visits and discomfort associated with the procedure; 
therefore, compliance may wane with time. A small percentage of patients may be ineligible 
for phlebotomy due to reduced venous access, congestive heart failure, or anemia. Oral iron 
chelation therapy will provide another option for patients either unwilling or unable to 
undergo a regular phlebotomy regimen.


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The aim of this study is to evaluate the efficacy and safety of deferasirox FCT versus 
phlebotomy for the management of iron overload in adults with HH at risk of iron-related 
morbidity. This evaluation will provide information on the two treatment options in terms of 
the response rate of proportion of patients reaching the study target SF ≤ 100 μg/L and their 
associated safety profiles.  
Ocular disturbances have been reported with deferasirox. Although no additional ocular risk 
have emerged over 10 years of Exjade on the market and from clinical trials, the FDA 
requires further confirmation on ocular safety with a controlled study in chelation-naive 
patients. Therefore, in addition to exploring the safety and efficacy of deferasirox FCT in HH, 
this study is being conducted to fulfill an FDA post-marketing requirement [PMC 750-10 
(Exjade) /PMR 2888-8 (Jadenu)] to provide additional randomized data to confirm the ocular 
safety profile of deferasirox through detailed ophthalmologic assessments in patients treated 
with deferasirox FCT for 2 years.  
2.2
Rationale for the study design
This will be an open-label design since phlebotomy cannot be blinded. The safety and 
response rate of deferasirox versus the standard of care phlebotomy in reducing iron in adult 
patients with HH will be evaluated.  
Patients will be randomized 2:1 to deferasirox FCT or phlebotomy.
2.3
Rationale for dose and regimen selection
A Phase I/II dose escalation study in HH (CICL670A2202), deferasirox DT 10 to 15 
mg/kg/day had an acceptable safety profile (Phatak 2010).  In a one-year Phase 2 study in HH 
patients (CICL670EBR14T), deferasirox DT 10±5 mg/kg/day was well tolerated and effective 
in reducing iron burden (Cancado 2015). Based on these 2 studies, the starting dose in this 
trial will be deferasirox FCT 7 mg/kg/day (equivalent to deferasirox DT 10 mg/kg/day). A 
dose adjustment between the two formulations is required because bioavailability was 
increased in FCT, and an equivalent deferasirox AUC was achieved at a lower dose, e.g., 
1080 mg FCT vs. 1500 mg DT (CICL670F2102 study).
2.4
Rationale for choice of combination drugs
Not applicable
2.5
Rationale for choice of comparators drugs
The control arm is phlebotomy which is the standard of care for removing excess iron in non-
anemic patients with HH. Most have unimpaired erythropoiesis so as blood is extracted, bone 
marrow is stimulated to make new red cells.  Iron stores are reduced when iron is transported 
to make hemoglobin.


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Depending on the hematocrit, each unit of blood (typically 500 mL) contains 200-250 mg iron 
and removal by phlebotomy decreases the ferritin level by approximately 30 µg/L (Bacon 
1997).  When SF is above normal, consensus opinion is that there is a benefit in early iron 
removal on a weekly or biweekly basis until iron stores are in the normal range (SF = 50-100 
µg/L), then thereafter, every two to four months to prevent re-accumulation of iron absorbed 
from a regular diet (EASL 2010, Tavill 2001).  Although there are no evidence-based studies,  
SF is the accepted standard for initiating and monitoring response to achieve a SF ≤ 100 μg/L, 
which is used as the primary endpoint of this study. Phlebotomy will be conducted at a 
frequency determined by the investigator's clinical practice.
2.6
Risks and benefits 
Appropriate eligibility criteria and specific dose modification and stopping rules are included 
in this protocol. Risk is minimized by compliance with the eligibility criteria and study 
procedures, close clinical monitoring, and protocol-defined dose modification rules. The 
available clinical trial data with FCT suggests a safety and efficacy profile consistent with the 
known profile of the DT formulation. As with any treatment or procedure, deferasirox FCT or 
phlebotomy may cause unforeseen risks, which could be serious.
The efficacy and safety of deferasirox have been evaluated in a large prospective clinical trials 
program that has generated long-term data in iron overload patients with transfusional iron 
overload (thalassemia major, sickle cell disease, and myelodysplasia syndrome) (Cappellini 
2006, Vichinsky 2007) and with non-transfusion dependent thalassemia. The accumulated 
data provides an acceptable safety and tolerability profile across all age groups. The majority 
of adverse events (AEs) are mild to moderate and manageable with dose adjustments or 
interruptions. The available clinical trial data with FCT suggests a safety and efficacy profile 
consistent with the known profile of the DT formulation. 
No new safety concerns regarding ocular toxicity have emerged since the approval of 
deferasirox. The most common visual acuity events were blurred vision and visual 
impairment.  The most common lens opacity was cataract, and retinal changes were due to 
degeneration, retinopathy, maculopathy or optic neuritis. As stated in the current Exjade and 
Jadenu USPIs, ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, 
and retinal disorders) were reported at a frequency of <1% with deferasirox therapy in the 
clinical studies. Optic neuritis occurs in 0.01% to 0.1% of patients. Ocular safety is a key 
secondary endpoint in this study, and ocular assessments are required to gather safety 
information.
In the dose escalation study in HH (ICL670A2202), elevations in liver transaminases and in 
serum creatinine were observed in a few patients, mainly those with a baseline SF < 1000 
µg/L who received an initial deferasirox DT dose of 15 mg/kg/day.  There are also post-
marketing reports of elevated liver transaminases and serum creatinine in those who continued 
to receive deferasirox when SF was < 100 µg/L. In this study, phlebotomy and drug will be 
held for a SF ≤ 100 µg/L, the lowest level believed to be safe to chelate with deferasirox.


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The AE profile in the above phase I/II HH study was consistent with the deferasirox 
registration studies in transfusional iron overload and post-marketing surveillance reports. 
The control arm phlebotomy is the standard of care in HH and does not pose an unexpected 
risk in this population. An oral iron chelation therapy may provide an option for patients 
either unwilling or unable to undergo a regular phlebotomy regimen.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
Assess the response rate in the deferasirox FCT and 
phlebotomy treatment arms where response is defined 
by achieving target SF ≤ 100 μg/L on or before 24 
months.
Proportion of patients achieving target SF ≤ 100 μg/L 
for the first time.
Key Secondary
Refer to Section 10.5.1
Characterize the ocular safety of deferasirox FCT and 
phlebotomy over 24 months.
Incidence of ocular AEs overall and by severity, type 
of AE, and relation to study treatment.
Secondary
Refer to Section 10.5.2 and Section 10.5.3
Evaluate the safety and tolerability of deferasirox FCT 
and phlebotomy over 24 months.
Incidence of AEs, AEs leading to discontinuation from 
study, laboratory abnormalities, and deaths.
Assess the change from baseline in visual acuity, 
intra-ocular pressure, retina or/and optic nerve 
abnormalities, and lens abnormalities at months 6, 12, 
18, and 24 of deferasirox FCT and phlebotomy.
Change from baseline at months 6, 12, 18 and 24 in 
visual acuity, tonometry, slit lamp, and fundus exams.
Assess the safety and tolerability of deferasirox FCT in 
patients who interrupt and re-initiate treatment due to 
SF levels ≤ 100 μg/L and ≥ 300 μg/L.
Incidence of AEs in patients who interrupt due to 
reaching target SF 
≤ 100 μg/L, then re-initiate therapy at ≥ 300 μg/L.
Assess the first time to response (defined as SF ≤ 100 
μg/L) between the deferasirox and phlebotomy 
treatment groups.
Time to reach target SF ≤ 100 μg/L in the deferasirox 
and phlebotomy arms for the first time.


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4
Study design
4.1
Description of study design
This is a Phase II, multicenter, open-label, randomized two-year study in 150 adults 
confirmed by HH genotype with iron overload. Eligible patients will be identified during a 4-
week screening period, then randomized in a 2:1 ratio (100 patients to deferasirox FCT and 50 
patients to phlebotomy), and treated for 24 months (104 weeks).  After end of treatment 
(EOT), there is a standard 30-day safety follow-up.  Please refer to Section 7 for screening 
and assessment details.
Figure 4-1
Study schema
An initial dose of deferasirox FCT 7 mg/kg/day will be used for 3 months (12 weeks), then 
adjusted according to the ferritin level. Dose adjustments based on safety are allowed at any 
time.
Phlebotomy will be conducted at a frequency determined by the physician.
Both phlebotomy and deferasirox FCT must be interrupted when the study-defined target SF 
≤ 100 μg/L is achieved. Deferasirox FCT may be reinitiated when SF ≥ 300 μg/L, according 
to deferasirox label; phlebotomy may be reinitiated when SF > 100 μg/L, based on standard of 
care practice. Following end of treatment, patients will enter a 30-day safety follow-up period. 
Concomitant medications and AEs will be collected during this period.
4.1.1
Post-treatment Ocular Follow-up
If a patient discontinues from treatment in either arm and has completed at least 6 months of 
assessments, they will be encouraged to continue in a Post-treatment Ocular Follow-up phase 
to undergo scheduled ocular exams every 6 months to receive at least 5 ophthalmological 
examinations. If a patient discontinues between
the scheduled 6-month exams, an 
ophthalmologic exam is part of the EOT and they will continue their regular schedule of 
ophthalmological exams every 6 months for a total of 6 ocular examinations. Please refer to 


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Section 7.2.2.5 for details.  One month prior to each ophthalmological visit, a site coordinator 
will call to confirm the upcoming visit. 
4.2
Timing of interim analyses and design adaptations
Not applicable
4.3
Definition of end of study
The end of study (EOS) will be when the latest of the following will have occurred: 
A) All patients completed 24 months of treatment, and patients completed their EOT visits 
and 30-day safety follow-up; OR 
B) Patients who discontinued from treatment prior to 6 months, or after 6 months but did not 
agree to participate in Post-treatment ocular follow-up: patients completed their EOT 
visits and 30-day safety follow-up; OR 
C) Patients who discontinued from treatment after 6 months and agreed to Post-treatment 
ocular follow-up: patients completed their EOT visits, 30-day safety follow-up, and Post-
treatment ocular follow-up up to Month 24.
After completing the study or discontinuing from study treatment, patients will receive 
standard of care. The primary analysis will be based on the final locked data and will be 
summarized in the clinical study report (CSR).  
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. If this occurs, the patient 
should be seen as soon as possible and the same assessments should be performed as 
described in Section 7.1.5 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
One hundred and fifty adult HH patients with homozygous C282Y genotype and iron 
overload (based on elevated transferrin saturation and SF) may enroll if they meet all 
inclusion and none of the exclusion criteria.
5.2
Inclusion criteria
Written informed consent must be obtained prior to any screening procedures.


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Patients eligible for inclusion must meet all following criteria prior to receiving study 
treatment:
1. Male or female ≥ 18-years-old
2. Documented genotype testing confirming homozygous for the C282Y mutation 
(C282Y/C282Y)
3. Transferrin saturation ≥ 45% (at either screening visit)
4. Serum ferritin (SF) ≥ 500 μg/L (at either screening visit)
5.3
Exclusion criteria
1. Medical conditions that preclude inclusion:

Iron overload not due to HH

Condition which might significantly alter the absorption, distribution, metabolism or 
excretion of oral deferasirox

Systemic disease which prevents taking study treatment or any contraindication to 
phlebotomy

Inflammatory condition or immunological disease which may interfere with the SF 
interpretation, such as an active infection, collagen vascular disorders, irritable bowel  
syndrome, lupus, or immune thrombocytopenia

Significantly impaired gastrointestinal function or disease that may significantly alter 
the absorption of oral deferasirox, e.g. ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection. 

Psychiatric or addictive disorder which prevent giving informed consent or 
undergoing any of the treatment options or unwilling or unable to comply with the 
protocol

Uncontrolled or significant cardiac disease or symptomatic cardiac arrhythmias, e.g., 
sustained ventricular tachycardia and clinically significant second or third degree AV 
block without a pacemaker. 

Illicit drug use and/or alcohol use, defined as an average alcohol consumption greater than 
one standard drink a day for women or two standard drinks a day for men within the 12 
months prior to enrolment. A standard drink is generally considered to be 12 ounces (or 
355 ml) of beer, 5 ounces (or 148 ml) of wine, or 1.5 ounces (or 44 ml) of 80-proof 
distilled spirits

Cirrhosis, including Child-Pugh class A, B, and C, diagnosed by liver biopsy, 
elastography, radiologic exams, or clinical criteria

Active hepatitis B or C (hepatitis B carrier will be allowed)

History of HIV seropositivity (ELISA or Western blot)

Organ transplant recipient


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
Malignancy of any organ system, treated or untreated, within the past 5 years whether 
or not there is evidence of local recurrence or metastases, except localized basal cell 
carcinoma of the skin, Hepatocellular carcinoma at any time is excluded.
2. Concomitant therapy that precludes enrollment:

Prior iron chelation therapy

Prohibited concomitant medications with deferasirox (see Section 6.4.3 for details)
3. Abnormal laboratory values:

Significant anemia that contraindicates phlebotomy (males with hemoglobin < 130g/L, 
females with hemoglobin < 120g/L) in both screening visit samples

Platelets ≤ 50 x 109/L in both screening visit samples

Urine protein/urine creatinine ratio > 1.0 mg/mg in both non-first void urine screening 
visit samples

Creatinine clearance ≤ 40 ml/min, or use the locally approved contraindication limit 
in prescribing information if it is stricter, in both screening visit samples 

Serum creatinine > 1.5 x ULN in both screening visit samples 

ALT ≥ 5 x ULN in both screening visit samples

Total bilirubin > 1.5 x ULN in both screening visit samples
4. Participation in an investigational study:

Observational registry study is allowable

Within 30 days prior to enrollment or within 5-half-lives of an investigational product, 
whichever is longer
5. Pregnancy and contraception:

Pregnant or nursing (lactating) women
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless using appropriate methods of contraception Deferasirox may 
reduce the efficacy of hormonal contraception, thus it is recommended to use alternative 
methods of contraception such as

Total abstinence
Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are unacceptable methods. 

Female sterilization (bilateral oophorectomy with or without hysterectomy), total 
hysterectomy, or tubal ligation at least six weeks before taking study treatment.  
If oophorectomy alone, hormone levels must confirm menopause.

Male sterilization (at least 6 months prior to screening). The vasectomized male 
must be the sole partner.  

Barrier methods of contraception:  condom or occlusive cap
For UK:  spermicidal foam/gel/film/cream/vaginal suppository


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
Placement of an intrauterine device or intrauterine system

Women considered as post-menopausal and not of childbearing potential are allowed 
to be enrolled in the trial if they have had 12 months of natural (spontaneous) 
amenorrhea with an expected clinical profile, e.g., age appropriate and history of 
vasomotor symptoms.
See Section 8.4 for pregnancy reporting and follow-up requirements.
6
Treatment
6.1
Study treatment
The sponsor will provide the open-label study medication oral deferasirox FCT tablets:  90 
mg, 180 mg and 360 mg. The control arm will undergo phlebotomy at intervals determined by 
the treating physician’s clinical assessment for optimal iron control.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Deferasirox FCT
Tablet for oral use
7 mg/kg (Initial dose)
Daily
Phlebotomy
Venipuncture
NA
determined by PI
After a 4-week screening period, eligible patients will be randomized 2:1 to receive 
deferasirox FCT or phlebotomy.
Patients randomized to deferasirox FCT will receive 7 mg/kg once daily. The daily dose is 
calculated based on the patient’s weight, 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). After 3 months (12 weeks), adjust dose as needed based on SF levels 
listed below with the maximum dose adjustment of 3.5 mg/kg/day per month.

SF < 300 μg/L 
Decrease to 3.5 mg/kg/day

SF 300-1000 μg/L
Maintain 7 mg/kg/day

SF > 1000-2000 μg/L
Increase to 10.5 mg/kg/day

SF > 2000 μg/L
Increase to 14 mg/kg/day 
When SF reaches the study target ≤ 100 μg/L, deferasirox FCT must be interrupted and the 
patient enters the maintenance phase. 
During the maintenance phase, when SF ≥ 300 μg/L, deferasirox FCT 3.5 mg/kg/day may be 
re-initiated.  If deferasirox FCT 3.5 mg/kg/day is not controlling SF and it continues to 
increase, increase to a maximum 7 mg/kg/day. Treat until the SF reaches ≤ 100 μg/L, then 
interrupt treatment again. 


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During regular study visits, the investigator or pharmacist will dispense the appropriate 
number of deferasirox FCT tablets to each patient. The number of tablets of each strength 
dispensed will be recorded in the study Drug Dosing Log. Each time deferasirox FCT is 
dispensed, the investigator must provide detailed instructions to patients, instruct them to take 
the assigned amount of study drug, and return all unused study medication every 4 weeks. 
Returned study medication must be counted and recorded. The field monitor must note the 
drug accountability during site visits and at the completion of the trial.
Medication labels must be in the local language and comply with the legal requirements of the
countries where the study is implemented.  Labels will have study identifier and storage 
conditions for the study drug, but no patient information.
Patients should swallow the required number of deferasirox FCT, with or without a light meal, 
and around the same time each day.
Patients should not make up missed doses. A missed dose is when the full dose is not taken 
within 8 hours of the usual time of the daily dose. Omit that day's dose, and resume with the 
next scheduled dose.  
Dose adjustments for safety are allowed at any time and must be in increments or decrements 
of 3.5 or 7 mg/kg/day. For this study, the maximum dose of deferasirox FCT is 14 mg/kg/day. 
Patients randomized to phlebotomy will receive treatment at a frequency determined by the 
treating physician’s judgment for optimal iron control. Phlebotomy must be interrupted when 
a patient achieves the target SF ≤ 100 μg/L. Treatment may be re-initiated when SF > 100 
μg/L.
Patients randomized to deferasirox FCT are not allowed to receive phlebotomy during the 
study treatment.
Patients randomized to the deferasirox FCT arm who discontinued from treatment may 
receive phlebotomy during Post-treatment Ocular Follow-up at a frequency determined by the 
physician.
6.1.2
Ancillary treatments
Not applicable
6.1.3
Rescue medication
Not applicable
6.1.4
Guidelines for continuation of treatment
Not applicable


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6.1.5
Treatment duration
The total duration of treatment for each patient is up to 24 months (104 weeks). The total 
duration of the study for each patient is approximately 26 months (4-week Screening, 104-
week Treatment, and 30-day Safety Follow-up).
6.2
Dose escalation guidelines 
Not applicable
6.3
Dose modifications 
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment of deferasirox FCT.
These dose modifications are summarized in Table 6-2. Deviations from the mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation of 
deferasirox FCT is mandatory for specific events indicated in Table 6-2 or listed in Section 
7.1.5.
These dose changes must be recorded on the Dosage Administration Record eCRF. It is 
important to keep an accurate dose adjustment records to enable an adequate evaluation of 
exposure.
Phlebotomy will be conducted at a frequency determined by the treating physician’s clinical 
judgement for optimal iron control. The name of the facility, the date of phlebotomy, 
hematocrit level prior to phlebotomy and amount of blood withdrawn must be captured in  
Phlebotomy Record and local lab eCRFs. Phlebotomy must be interrupted when SF ≤ 100 
μg/L and may be resumed when SF > 100 μg/L. 


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Table 6-2
Criteria for dose reduction / interruption and re-initiation of deferasirox FCT 
Dose modifications for ICL670F2203
Serum Ferritin (SF)
After an initial starting dose (7 mg/kg/day) for 3 months 
(12 weeks), dose may be adjusted based on SF level.  
Dose increase cannot be more than 3.5 mg/kg/day at 
each adjustment.
<300 μg/L
Decrease to 3.5 mg/kg/day
300-1000 μg/L
Maintain 7 mg/kg/day
>1000-2000 μg/L
Increase to 10.5 mg/kg/day
>2000 μg/L
Increase to 14 mg/kg/day (higher doses are not allowed.)
SF ≤ 100 μg/L at any time
Interrupt deferasirox FCT
SF ≥ 300 μg/L after dose interruption
Re-initiate deferasirox FCT 3.5 mg/kg/day.  If SF continues to increase, increase to 7 mg/kg/day (maximum 
dose for maintenance phase).
Body Weight
Increase/decrease if weight changes >10% compared to 
baseline weight or weight at last dose adjustment due to a 
change in weight
Dose of study medication will be adapted using Dosing Table (provided in Appendix 14.1)
When weight changes >10% compared to baseline weight or weight at last dose adjustment due to a change 
in weight, re-calculate dose. Smaller variations in weight (<10%) do not require dose adjustments. 
Investigations (Renal)
Serum creatinine
Single increase 
Maintain dose and repeat assessment at next visit.
Increased creatinine ≥ 33% from baseline (average of 2 
samples) resulting in creatinine > ULN x 2 consecutive 
samples (at least 2 weeks apart)
Decrease by 7 mg/kg/day or interrupt if already at 7 mg/kg/day or lower.
If dose is decreased, but increasing creatinine > ULN
Interrupt treatment.
After interruption, if creatinine returns to within normal 
limits on 2 consecutive visits.
Resume 50% of the most recent dose prior to interruption.  
If after another 4 weeks, creatinine remains stable, resume 100% dose (adjust for weight if needed). 
Creatinine clearance ˃ 40 and ˂ 60 mL/min
Caution in patients if there are additional risk factors that may impair renal function, such as concomitant 
medications, dehydration, or severe infection.


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Creatinine clearance < 40 mL/min 
or increased serum creatinine > 2x age-appropriate ULN
Deferasirox must be discontinued.
Urine protein/creatinine ratio
Any proteinuria 
If new or worsening pre-existing proteinuria (assessed by dipstick), collect a urine sample for assessment by 
the central/local laboratory.
In case of a single increase of the urinary protein/creatinine ratio, repeat the assessment at the next visit.
> 0.5 urine protein/ creatinine ratio (mg/mg) in two 
consecutive non-first void urine samples (a minimum of 
48h apart), if all other causes of proteinuria have been 
excluded.
Decrease deferasirox by 50%.
If UPCR resolves (< 0.5mg/mg) at the next study visit, resume 100% dose. 
> 1.0 (mg/mg) in two consecutive non-first void urine 
samples (a minimum of 48h apart)
Interrupt deferasirox FCT.
If the increased UPCR resolves (< 0.5 mg/mg) at the next study visit, resume dose at 50% of the last dose.   
If UPCR remains within normal limits after 4 weeks at the 50% reduced dose, resume study medication at 
100% of the last dose.
Persistent proteinuria
If proteinuria persists, discontinue study treatment if the investigator believes it is in the best interest of the 
patient. 
Novartis may be contacted by the investigator to discuss dosing options.
Dose adjustment must be based on central/local laboratory results.
Investigations (Hepatic) 
Isolated direct (conjugated) Bilirubin elevation
> ULN – 1.5 x ULN
Maintain dose
> 1.5 - 3.0 x ULN 
Interrupt dosing.  Monitor  LFTsa weekly or more frequently if clinically indicated until resolved to ≤ 1.5 x 
ULN:
If resolved ≤ 14 days, then maintain dose.
If resolved > 14 days, then ↓1 dose level (3.5 mg/kg/day FCT)
> 3.0 - 10.0 x ULN* 
Interrupt dosing.  Monitor  LFTsa weekly or more frequently if clinically indicated until resolved ≤ 1.5 x ULN:
If resolved ≤ 14 days, then ↓ 1 dose level (3.5 mg/kg/day FCT)
If resolved > 14 days, then discontinue patient from study drug.  The patient must be monitored weekly 
(including LFTsa), or more frequently if clinically indicated until total bilirubin resolves to baseline or stabilizes 
over 4 weeks. 


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> 10.0 x ULN*
Discontinue patient from study drug 
The patient must be monitored weekly (including LFTsa) or more frequently if clinically indicated until total 
bilirubin resolves to baseline or stabilizes over 4 weeks.
Isolated AST or ALT elevation 
> ULN - 3.0 x ULN
Maintain dose 
> 3.0 - 5.0 x ULN 
For patients with baseline  ≤ 3.0 x ULN
For patients with baseline  > 3.0 - 5.0 x ULN
Maintain dose.  Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of 
abnormal results. If abnormal lab values are confirmed upon a repeat test, then monitor LFTsa weekly or 
more frequently if clinically indicated until resolves ≤ 3.0 x ULN.
Maintain dose 
> 5.0 - 10.0 x ULN
For patients with baseline  ≤ 3.0 x ULN
Baseline > 3.0 -5.0 x ULN
Omit dose.  Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of abnormal 
results. Monitor LFTsa weekly or more frequently if clinically indicated until resolves ≤ 3.0 x ULN.
If resolved ≤ 14 days, maintain dose.
If resolved > 14 days, ↓ 1 dose level (3.5 mg/kg/day FCT).
Maintain dose. Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of 
abnormal results.  If abnormal lab values are confirmed upon a repeat test, then monitor LFTsa weekly, or 
more frequently if clinically indicated until resolved to ≤ 5.0 x ULN.  
> 10.0 - 20.0 x ULN 
Omit dose.  Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of abnormal 
results. Monitor LFTsa weekly, or more frequently if clinically indicated until resolved to ≤ baseline, then↓ 1 
dose level (3.5 mg/kg/day FCT).
> 20.0 x ULN
Discontinue patient from study drug.
Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of abnormal results. 
Monitor LFTsa weekly or more frequently if clinically indicated until resolved to baseline or stabilization over 4 
weeks.
Combinedb AST or ALT and total bilirubin elevations
Normal baseline ALT and AST and  total bilirubin:
AST or ALT > 3.0 x ULN with total bilirubin > 2.0 x ULN 
without evidence of cholestasisc
OR  
Permanently discontinue deferasirox. 


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In patients with elevated baseline AST or ALT or  total 
bilirubin:
[AST or ALT > 2x baseline AND > 3.0 x ULN]  OR
[AST or ALT > 8.0 x ULN], combined with [total bilirubin > 
2x baseline AND > 2.0 x ULN]
Repeat as soon as possible, preferably within 48 hours from awareness of abnormal results. Monitor LFTsa
weekly or more frequently if clinically indicated until AST, ALT, or bilirubin resolve to baseline or stabilize 
over 4 weeks.  Refer to Section 6.3.3.1 for additional follow-up evaluations as applicable.
Hepatic Impairment
Moderate hepatic impairment (Child-Pugh Class B)
Interrupt deferasirox and monitor patient. If liver disease prognosis improves, re-start deferasirox 7 
mg/kg/day FCT or 50% of previous dose, whichever is less. Increase dose 3.5 mg/kg/day FCT every 2 
weeks to a maximum of 50% of previous dose if the investigator determines that the dose increase is in the 
best interest of the patient. 
Severe hepatic impairment (Child-Pugh Class C)
Discontinue deferasirox.
Skin and subcutaneous tissue disorders
Severe skin reaction
Severe skin reactions, including Stevens-Johnson
syndrome (SJS) and Toxic epidermal necrosis (TEN)
Drug reaction with eosinophilia and systemic symptoms 
(DRESS)
Deferasirox must be immediately discontinued and not reintroduced
Skin rash (other than SJS)
Mild/moderate severity (minimal symptoms which require 
no or minimal supportive treatment)
Continue study drug without dose adjustment. If the rash persists >1 week or becomes more severe, 
interrupt dosing.
After the rash resolves, resume study drug at 50% of last dose. If the rash does not recur, increase dose to 
100% of dose after 2 weeks.
Severe rash (distressing symptoms requiring
interruption of study medication and/or systemic steroids)
Interrupt treatment until resolution of rash.
After the rash resolves, resume at 50% dose. If necessary, a brief course of oral steroids may be given 
concurrently with resumption of study drug. If the rash does not recur, increase in steps of 3.5 mg/kg/day for 
deferasirox FCT every 2 weeks until last dose is achieved. If the rash recurs, discontinue study treatment.
Other adverse events
Dose modification criteria for auditory and ocular disturbances
Auditory (decreased hearing) and ocular (lens opacities) 
disturbances have been reported with deferasirox.
Auditory and ophthalmic testing (including funduscopy) is required before starting deferasirox.
If disturbances are noted, consider reducing the dose or interruption. Repeat testing may be done per 
investigator’s judgement.


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Dose modification criteria for hypersensitivity reactions
Cases of serious hypersensitivity reactions, such as 
anaphylaxis and angioedema, have been reported in 
patients receiving deferasirox.  In the majority of cases, 
onset of the reaction occurred within the first month of 
treatment.
If reactions are severe, discontinue deferasirox and institute appropriate medical intervention.
Due to the risk of anaphylactic shock, do not reintroduce deferasirox in patients who have experienced 
previous hypersensitivity reactions.
Dose modification criteria for cytopenias
Unexpected Cytopenias
Post-marketing reports (both spontaneous and from clinical trials) of cytopenias occurred mostly in patients 
with pre-existing hematological disorders and were frequently associated with bone marrow failure. Their 
relationship with deferasirox was uncertain. The standard clinical management of such hematological 
disorders is regular monitoring of complete blood count.
Consider interrupting deferasirox for unexplained cytopenia.
Consider reintroducing deferasirox once the cause of cytopenia is identified.
Gastrointestinal disturbances
Diarrhea, constipation, nausea, vomiting and abdominal 
pain.
At the first sign of diarrhea**, consider an anti-diarrheal medication, such as loperamide.  Discontinue any 
laxative or stool softener and eat small, frequent meals.
If appropriate, maintain adequate hydration with approximately 8 glasses of water per day.  If the 
gastrointestinal issues (diarrhea, constipation, nausea, vomiting and abdominal pain) persist, discontinue 
study drug if the investigator believes that is in the best interest of the patient.
All dose modifications should be based on the worst preceding toxicity.
a. Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect] if total bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.)
b. “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total bilirubin and 
isolated elevation of AST/ALT, and take conservative action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed 
for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the defined thresholds that allow treatment re-initiation, re-
start treatment either at the same dose or at one dose lower if criterion is met for dose reduction.
c.
“Cholestasis” defined as alkaline phosphatase elevation (> 2.0 x ULN and R < 2 ) in patients.
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional guidelines 
(e.g., review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose and continue treatment at the discretion of the investigator.
** Note: anti-diarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea.


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6.3.2
Dose adjustments for QTcF prolongation
Not applicable
6.3.3
Follow-up for toxicities
If treatment is interrupted due to an AE or abnormal laboratory value, patients must be 
followed at least once a week for 4 weeks and subsequently at approximately 4 week intervals, 
until resolution or stabilization of the event, whichever comes first. If treatment is 
permanently discontinued due to an AE or abnormal laboratory value (that meets criteria for 
an AE or SAE), patients must be followed for at least 30 days following the last dose of 
treatment. All patients must be followed for an AE and SAE for 30 days following the last 
dose of treatment.
6.3.3.1
Follow up on potential drug-induced liver injury (DILI) cases
Increases in ALT and AST with an elevated total bilirubin can be seen in advanced stage HH, 
but is uncommon.
Increases in ALT and AST with an increased total bilirubin may be indicative of a potential 
DILI and should be considered as a clinically important event. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and total 
bilirubin value; patients meeting any of the following criteria will require further follow-up as 
outlined below:

Baseline normal ALT and AST and total bilirubin: AST or ALT > 3.0 x ULN combined 
with total bilirubin > 2.0 x ULN

Elevated baseline AST or ALT or total bilirubin: [AST or ALT > 2 x baseline AND > 3.0 
x ULN] OR [AST or ALT > 8.0 x ULN] combined with [total bilirubin > 2 x baseline 
AND > 2.0 x ULN]

Normal ALT and AST with increased total bilirubin:  rule out Gilbert’s syndrome, defined 
by increased indirect bilirubin.
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as alkaline phosphatase > 2.0 x ULN with R < 2 in patients.
Note: (R is calculated by ALT divided by alkaline phosphatase, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or alkaline phosphatase 
elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver 
injury.
In the absence of cholestasis, patients must immediately discontinue from study treatment and 
repeat LFTs as soon as possible, preferably within 48 hours from the awareness of abnormal 
results. Evaluation should include laboratory tests, detailed history, physical assessment and 
consideration of liver metastasis or new liver lesions, obstructions/compressions, etc. 


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1. Laboratory tests should include ALT, AST, albumin, creatinine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time/INR and alkaline phosphatase. 
2 . Collect detailed history, such as review of ethanol, concomitant medications, herbal 
remedies, supplement consumption, pre-existing liver conditions or risk factors.
3. Testing for acute hepatitis A, B, C or E infections and liver imaging (e.g. biliary tract) if 
warranted. 
4. Additional testing for other hepatotropic viral infections (CMV, EBV or HSV), 
autoimmune hepatitis or consultation with a hepatologist for liver biopsy if clinically 
indicated. 
All cases, confirmed on repeat testing, that meet the laboratory criteria defined above and 
have no other alternative cause for abnormal LFTs, must be considered “medically significant” 
and meeting the definition of SAE (Section 8.2.1) for reporting as an SAE using the term 
“potential drug-induced liver injury”. All events should be followed with the outcome clearly
documented.
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
The patient must be reminded to notify the investigational site about any new medications 
he/she takes after starting 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 or 
the Procedures and Significant Non-Drug Therapies eCRF.
6.4.2
Permitted concomitant therapy requiring caution and/or action
Concomitant administration of deferasirox and vitamin C has not been formally studied. 
Vitamin C up to 200 mg/day has not been associated with adverse consequences.
Caution must be exercised if taking deferasirox in combination with the following:

Drugs with a known ulcerogenic potential, such as NSAIDs, corticosteroids, oral 
bisphosphonates, or anticoagulants which may increase the risk of gastrointestinal 
irritation and bleeding

Deferasirox is a weak CYP3A4 inducer and may potentially decrease serum levels of 
substances metabolized through CYP3A4

Deferasirox is a moderate inhibitor of CYP2C8 and may increase serum levels of 
substances metabolized through CYP2C8 (e.g. repaglinide, paclitaxel).

Deferasirox can potentially increase the levels of substances metabolized through 
CYP1A2 (e.g. theophylline, clozapine, tizanidine). Monitor theophylline levels and 
consider theophylline dose reduction.


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
Potent UGT inducers (e.g. rifampicin, phenytoin, phenobarbital, ritonavir) may decrease 
deferasirox concentration.
6.4.3
Prohibited concomitant therapy

Aluminium-containing antacid therapies may bind to deferasirox.

Bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) decrease deferasirox 
systemic exposure.

Other iron chelators (deferoxamine, deferiprone, deferasirox) during study treatment and 
Post-treatment Ocular Follow-up phases

Any investigational drug other than study medication
6.4.4
Use of Bisphosphonates
Requires caution (See Section 6.4.2)
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is assigned a Subject Number (Subject No.) when enrolled for screening. It is 
retained as the primary identifier for the patient throughout his/her entire participation in the 
trial. 
 
 Upon signing the informed consent form (ICF), 
the patient is assigned to the 
Subject No. available to the investigator through 
the Clinical Data Management System interface.
The investigator or designated staff will contact the Interactive Response Technology (IRT) 
provider and register the patient. Once assigned, the Subject No. must not be reused for any 
other subject and the Subject No. for that individual must not be changed, even if the patient 
is re-screened. If the patient fails to be randomized or start treatment, the reason must be 
entered on the Screening Disposition page.
IRT must be notified within 2 days that the patient was not randomized.
6.5.2
Treatment assignment or randomization
Patients will be assigned to one of the two treatment arms (Section 4.1 and Section 6.1), 
deferasirox FCT or phlebotomy in a 2:1 ratio.
Randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the IRT 
provider using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization 


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list will be produced by or under the responsibility of Novartis Drug Supply Management 
using a validated system that automates the random assignment of medication numbers to 
medication packs containing the study treatment.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all inclusion/exclusion criteria. IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
6.5.3
Treatment blinding
This is an open-label study so investigators, patients, and sponsor will have full knowledge of 
treatment allocation. To minimize the potential impact of treatment knowledge, no aggregated 
statistical analyses (efficacy or safety) shall be performed by treatment (other than analyses 
specified in the protocol) until the primary analysis is conducted.
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 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
Study treatment, deferasirox FCT, will be provided from the global clinical open supply and 
will be packaged and labeled under the responsibility of Novartis Drug Supply Management. 
Study treatment labels will comply with the legal requirements of each country and will 
include storage conditions and a unique medication number (corresponding to study treatment 
and strength). They will supply no informaiton about the patient. Responsible site personnel 
will identify the study treatment package(s) to dispense by the medication number(s) assigned 
by IRT to the patient. Site personnel will add the patient number on the label. If the label has 
2 parts (base plus tear-off label), immediately before dispensing the package to the patient, 
site personnel will detach the outer part of the label from the package and affix it to the 
patient’s source document.
Table 6-3
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
deferasirox FCT
Tablets in bottles
Labeled as ‘ICL670’ 
Study treatment packaging has a 2-part label.


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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 deferasirox FCT 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
Compliance will be assessed by the investigator and/or study personnel at each patient visit. 
Information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a Drug Accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
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 (phlebotomy)
Patients randomized to the phlebotomy arm will go to a therapeutic phlebotomy center or 
hospital to receive treatment at a frequency that the investigator prescribes.  The investigator 
or designee must collect an accurate record of the name of facility, the date of phlebotomy, 
hematocrit level prior to phlebotomy and amount of blood withdrawn at each treatment. This 
information must be captured in the source document at each visit and recorded on the eCRF.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility as per local SOPs and 
regulations. Drug supply may be destroyed at the site if permitted by local regulations and 
authorized by Novartis in a prior agreement.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all assessments and indicates with an “X” the visits when they are performed. 
All data obtained from these assessments must be supported in the patient’s source 
documentation. 
Scheduled assessments should be done on the designated day, or as close to it as possible, i.e., 
not exceeding ± 3 days for assessments scheduled at Week 2 and Week 4, not exceeding ± 7 
days for monthly visits until Week 104 (End of Treatment Visit), and not exceeding ± 30 days 
for assessments done approximately every 6 months, such as ocular and ECG assessments. In 
this clinical trial, a week is 7 calendar days, and 1 month is 30 days. 
FRANCE SPECIFIC ONLY: The additional assessments of creatinine and creatinine 
clearance at Week 1 and Week 3 after start of treatment, and weekly checks of creatinine and 
creatinine clearance during the first month of dose increases, are specific to patients enrolled 
in sites from France. These assessments are NOT included in the Table 7-1, and should be 
recorded as unscheduled visits. 
No eCRF will be used as a source document. 


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Table 7-1
Visit evaluation schedule
Category
Protocol Section 
Screening
Randomization
Treatment Period
End of study treatment (EoT)
30-day Follow up
Post-treatment Follow-up *
Weeks
-4
-2
Day 1
2
4
8
12
16
20
24
28, 32, 36, 
40, 44, 48
52
56, 60, 
64, 68, 
72
76
80, 84, 88, 
92, 96, 100
104
108
Informed 
Consent
D
7.1.2
X
IRT Registration
S
7.1.2.1
X
Demography
D
7.1.2.3
X
Inclusion/
exclusion 
D
7.1.2
X
X
HH history
D
7.1.2
X
Medical History
D
7.1.2.3
X
Prior and 
concomitant 
medication / 
procedures
D
6.4
Continuously till 30 days after last dose of study treatment 
Ocular History
D
7.1.2.3
X


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Category
Protocol Section 
Screening
Randomization
Treatment Period
End of study treatment (EoT)
30-day Follow up
Post-treatment Follow-up *
Weeks
-4
-2
Day 1
2
4
8
12
16
20
24
28, 32, 36, 
40, 44, 48
52
56, 60, 
64, 68, 
72
76
80, 84, 88, 
92, 96, 100
104
108
Cirrhosis History
D
7.1.2
X
Randomization
D
6.5
X
Disposition
D
7.1.2
X
X
X
Molecular 
Testing of HH
D
7.2.2.6.1
X
Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Best Corrected 
Visual Acuity
D
7.2.2.5
X
X
X
X
X
X


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Category
Protocol Section 
Screening
Randomization
Treatment Period
End of study treatment (EoT)
30-day Follow up
Post-treatment Follow-up *
Weeks
-4
-2
Day 1
2
4
8
12
16
20
24
28, 32, 36, 
40, 44, 48
52
56, 60, 
64, 68, 
72
76
80, 84, 88, 
92, 96, 100
104
108
Slit Lamp Exam     
(w/ LOCS III)
D
7.2.2.5
X
X
X
X
X
X
Tonometry
D
7.2.2.5
X
X
X
X
X
X
Fundus 
Photography
D
7.2.2.5
X
X
X
X
X
X
ECG
D
7.2.2.7.1
X
X
X
X
X
Audiometry
D
7.2.2.4
X
X
X
X
X
Cirrhosis 
assessment
D
7.2.2.8
X
Hematology
D
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.2.6.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
D
7.2.2.6.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Category
Protocol Section 
Screening
Randomization
Treatment Period
End of study treatment (EoT)
30-day Follow up
Post-treatment Follow-up *
Weeks
-4
-2
Day 1
2
4
8
12
16
20
24
28, 32, 36, 
40, 44, 48
52
56, 60, 
64, 68, 
72
76
80, 84, 88, 
92, 96, 100
104
108
Urine 
protein/creatinine 
ratio
D
7.2.2.6.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Transferrin 
saturation
D
7.2.2.6.7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis tests
D
7.2.2.6.5
X
Serum Ferritin
D
7.2.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
Pregnancy 
D
7.2.2.6.8
X
Urine Pregnancy
D
7.2.2.6.8
X
X
Phlebotomy 
record
D
6.6.3.3
Continuously from 6 months before Randomization to End of study treatment.
Drug dispensing
S
6.6
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
administration
D
6.6
Daily intake of study drug


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Category
Protocol Section 
Screening
Randomization
Treatment Period
End of study treatment (EoT)
30-day Follow up
Post-treatment Follow-up *
Weeks
-4
-2
Day 1
2
4
8
12
16
20
24
28, 32, 36, 
40, 44, 48
52
56, 60, 
64, 68, 
72
76
80, 84, 88, 
92, 96, 100
104
108
Adverse events
D
8.1
Continuously after ICF signature and till 30 days after last dose of study treatment 
Follow-up on 
potential drug 
induced liver 
injury (DILI) 
cases
D
6.3.3.1
If there is a potential DILI, a detailed history, additional lab tests (creatinine kinase, gamma-glutamyl 
transpeptidase, and alkaline phosphatase), testing for acute hepatitis infection or other hepatotropic viral 
infection or autoimmune hepatitis should be considered.  This will be documented in an unscheduled visit.
*Post treatment follow up:  See Section 4.1.1
.


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7.1.1
Molecular pre-screening 
Not Applicable
7.1.2
Screening
Prior to screening, the patient must give full informed consent on the appropriate form. Once 
signed and dated by the patient, the investigator must review the study’s inclusion and 
exclusion criteria with the patient to ensure that the patient is eligible to participate.
Two Screening Visits (at -4 weeks and at -2 weeks) are needed to perform key safety 
parameters prior to first dose administration per the deferasirox drug label and to confirm 
eligibility criteria.
Molecular testing of HH must be performed at the first screening visit if historical diagnosis is 
not available.  
Specific safety assessments including ophthalmic and audiometry examinations, ECG, and 
cirrhosis assessment (unless diagnosis is available during the past 12 months, or SF is <1000 
μg/L and AST/ALT are normal) must be performed prior to starting study drug.  It is preferred 
that they are performed at the first screening visit (-4 weeks), but to make it possible for the 
site to plan the examinations properly, these assessments can be performed at the second 
screening visit (-2 weeks). 
SF, serum creatinine and urine protein/creatinine ratio will be measured at both screening 
visits and used to assess eligibility. SF should be obtained in the absence of any infection or 
inflammation.
Serum Pregnancy test will be required for females of child-bearing potential only.
The full list of assessments to be performed during screening is detailed in Table 7-1.
Re-screening is permissible on a case-by-case basis. All assessments at screening visits must 
be repeated if a patient is re-screened, except for molecular testing of HH, Ocular, 
Audiometry, ECG, and cirrhosis assessments. Please contact Novartis for guidance and see 
Section 7.1.2.2 on how to process screen failures.
7.1.2.1
Eligibility screening 
After registering in the IRT for screening, patient eligibility will be checked to ensure all 
screening procedures are completed. The eligibility check will be embedded in the IRT 
system. Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
Patients who sign an informed consent, but fail to get randomized for any reason will be 
considered a screen failure. The reason for not starting must be entered on the Screening 
Phase 
Disposition 
page. 
Demographic 
information, 
informed 
consent, 
and 


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Inclusion/Exclusion pages 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 an SAE during the Screening Phase (see Section 8.2 for SAE reporting details). If 
the patient fails to be randomized, the IRT must be notified within 2 days of the screen fail 
that the patient was not randomized.
7.1.2.3
Patient demographics and other baseline characteristics
Data will be collected on patient characteristics, including demographic information (age, sex, 
ethnicity, etc.) medical history/ current medical conditions, prior or current medication, ocular 
and phlebotomy history. Retrospective data on phlebotomy history will be collected from the 
6 months prior to randomization.
To determine eligibility, patients will undergo assessments per the inclusion and exclusion 
criteria, including molecular testing of HH if no historical diagnosis available, SF, transferrin 
saturation, hemoglobin, hematocrit, serum creatinine, total bilirubin, ALT/AST, hepatitis, 
further testing for HIV-positive (ELISA or Western blot), serum pregnancy, urinalysis, and 
weight.
Other assessments include ocular, audiometry, ECG, and cirrhosis assessment.
7.1.3
Run-in period
Not applicable
7.1.4
Treatment period
The study treatment duration is 24 months (104 weeks). Patient visits will occur bi-weekly for 
the first 4 weeks, then every 4 weeks from Week 4 until 104 (EOT).
All visits should be scheduled respective to the randomization date (Day 1), rather than in 
relation to previous visits.
After completing screening, eligible patients will be enrolled and randomized to receive 
phlebotomy or deferasirox FCT. For deferasirox FCT, the target daily dose is calculated by 
the physician based on the patient’s actual body weight.
At the start of treatment, patients randomized to deferasirox FCT will receive 7 mg/kg once 
daily. Patient randomized to phlebotomy may receive treatment at a frequency determined by 
the treating physician.
For details on study design and dose adjustments, see Section 4 and Section 6.3.
For details on assessments during the treatment period, see Table 7-1.
FRANCE SPECIFIC ONLY: The additional assessments of creatinine and creatinine 
clearance at Week 1 and Week 3 after start of treatment, and weekly checks of creatinine and 
creatinine clearance during the first month of dose increases, both specific to patients enrolled 


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in sites from France only, are NOT included in the Table 7-1, and should be regarded as 
unscheduled visits. 
7.1.5
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 must make a
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate eCRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for
visits, or become lost to follow-up for any other reason.
The investigator may discontinue study treatment for a given patient if; he/she believes that
continuation would be detrimental to the patient’s well-being.
Study treatment must also be discontinued under the following circumstances:
Pregnancy
AEs listed in Table 6-2
Laboratory abnormalities listed in Table 6-2
Unwillingness to comply with the prescribed study treatment
Use of prohibited treatment refer to Section 6.4.3
Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment should NOT be considered withdrawn from the
study. They should return for the assessments indicated in Section 7.2.2.5. If they fail to
return for these assessments for unknown reasons, every effort (e.g. telephone, email, letter)
should be made to contact them as specified in Section 7.1.8.
The investigator must also contact the IRT to register the patient’s discontinuation from 
study treatment.
7.1.5.1
Replacement policy 
Not Applicable
7.1.6
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject does not want to participate in the 
study any longer, and does not allow further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.


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Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used 
for further testing/analysis in accordance with the terms of this protocol and of the informed 
consent form.
For EU and Rest of World: All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements. Follow up for safety evaluations
7.1.7
Follow up for safety evaluations
All patients must have safety evaluations for 30 days after the last dose of study treatment. If 
death occurs during this period, this will be collected in the End of Treatment Disposition 
eCRF and Death eCRF.
Data collected should be added to the AEs eCRF and the Concomitant Medications eCRF.
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source document 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 must be recorded on the appropriate 
Disposition eCRF.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Serum Ferritin (SF)
In the absence of infection or inflammation, SF test will be performed at Screening visits (-4 
weeks and -2 weeks) to assess eligibility. Thereafter SF testing will be done at Day 1, Weeks 


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2, 4 and then every 4 weeks till week 104 (EOT) to assess the response rate of deferasirox 
FCT and phlebotomy. For efficacy evaluation, the last available assessment before or on the 
date of randomization is taken as the “baseline” value.
7.2.2
Safety and tolerability assessments
Safety will be monitored by physical examination, vital signs, ocular, audiometry, ECG and 
laboratory evaluations (please refer to Table 7-3), 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 the first screening visit, randomization and all 
subsequent visits. The physical examination at randomization (Day 1) will serve as the 
Baseline physical examination for the entire study. 
Physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological.
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 on the 
Medical History page of the patient’s eCRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the AE summary page.
7.2.2.2
Vital signs
Vital signs will be measured at screening and at subsequent time points specified in Table 7-1. 
Assessment includes blood pressure (supine position preferred when ECG is collected), 
respiratory rate, pulse, and temperature. 
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 specified in Table 7-1.
7.2.2.4
Auditory examination
Patients will undergo auditory examinations locally approximately every 6 months (Screening, 
Weeks 24, 52, 76, and 104). 
Interpretation of the audiometry examination must be made by a qualified physician and 
documented on the eCRF page.


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Information about the audiometry examinations must be present in the source documentation 
at study site. Significant abnormal findings that meet the definition of an AE must be recorded 
in the AE summary page of the eCRF.
7.2.2.5
Ocular examination
Ophthalmologic examinations must be conducted approximately every 6 months for at least 5 
ocular assessments at screening and Weeks 24, 52, 76, and 104 (EOT). 
An exception is for patients eligible for the Post-treatment Ocular Follow-up phase and EOT 
occurs in the interval between the scheduled 6-month exams (the allowed assessment window 
is 30 days +/- of the scheduled date), an ophthalmologic exam is part of the EOT then they 
will continue their regular schedule of ophthalmological exams every 6 months (recorded in 
Post-treatment follow-up eCRFs at Weeks 52, 76 and 104 as appropriate) for a total of 6 
ocular examinations. A reminder by the site at least one month prior to each upcoming 
ophthalmological visit should be made. To provide consistent assessments, it is recommended 
that ocular assessments be performed at the same site with the same equipment for each 
patient.
The ophthalmologic examination includes the following assessments:

Best corrected visual acuity must be done using Early Treatment Diabetic Retinopathy 
Study (ETDRS) 

Slit lamp examination:  any opacity graded using the Lens Opacities Classification System, 
version III (LOCS III)

Intraocular pressure (IOP) measured by tonometry should be performed after the above 
two ocular tests

Dilated fundus exam and color fundus photography
The dilated fundus exam must assess the vitreous, retina, macula, and optic nerve for both 
eyes. Wide-angle fundus photography of the retina and optic nerve is preferred; however, if 
unavailable, a regular camera capturing 7 standard stereoscopic fields is allowed.
Detailed instructions for the ophthalmic assessments are provided in the “Manual of 
Ophthalmic Procedures”.
Table 7-2
Central imaging assessments collection plan
Procedure
Baseline
During Treatment
Color Fundus Photography
Required
Every 6 months (Screening and 
weeks 24, 52, 76, and 104)
The ocular examination will be performed by a local, qualified ophthalmologist and the 
results will be documented on the eCRF page. The color fundus photography will not be 
reported locally and instead be sent to an imaging Contract Research Organization (CRO) 
designated by Novartis for reading.


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Details on transferring the color fundus photographs for reading by the imaging CRO are 
provided to investigators in the imaging CRO Site Operations Manual. The imaging CRO will 
maintain both the original source images as well as any alterations made to the images during 
interpretation. All details of the central review methodology will be described in the Central 
Imaging Review Charter. 
Information and results of the local ocular examination must be present in the source 
documentation at the study site. Significant abnormal findings affecting the normal function 
of the eye or its structure, detected and diagnosed or verified by an ophthalmologist, which 
also meet the definition of an AE must be recorded in the AE summary page of the eCRF. 
7.2.2.6
Laboratory evaluations
Table 7-3
Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White 
blood cells, RBC morphology, Differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, bands)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Bicarbonate, Calcium, Magnesium, 
Phosphorus,  Chloride, Sodium, Potassium, Creatinine, Creatinine kinase, Direct 
(conjugated) Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, Lactate 
Dehydrogenase, Blood Urea Nitrogen, Uric Acid, Amylase, Lipase, Glucose 
(non-fasting)
Urinalysis
Microscopic Panel (red blood cells, white blood cells, casts, crystals, bacteria, 
epithelial cells) performed if a positive dipstick
Macroscopic Panel (dipstick supplied by the central lab and performed by site): 
color, bilirubin, blood, glucose, ketones, leukocyte esterase, nitrite, pH, protein, 
specific gravity, urobilinogen
Coagulation
International normalized ratio 
Hepatitis markers
HbsAg, HbsAb, HbcAb, HCV RNA, Anti-HCV
Additional tests
Serum ferritin, Creatinine clearance, Urine protein/creatinine ratio, Transferrin 
saturation (fasting), Molecular testing for HH.
Pregnancy Test
Serum pregnancy test, urine pregnancy test. 
A central laboratory will be used for analysis of all specimens collected, except urinary 
dipstick analysis and urinary pregnancy test will be performed by the local lab.
Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the Central Laboratory Manual.
Local laboratory assessments may be performed if medically indicated or when the treating 
physician cannot wait for central laboratory results for decision-making. In this situation, a 
second blood sample obtained at the same time should be submitted to the central laboratory 
for analysis in parallel with local analysis. 
Results of the local laboratory will be recorded in the eCRF if the following criteria are met:


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
Treatment decision was made based on the local results, or

No concomitant central lab results are available
Eligibility into the study will be based on central laboratory results. 
7.2.2.6.1 Molecular test for HH
Blood samples for molecular testing of HH must be collected at the first screening visit if no 
historical diagnosis available.
7.2.2.6.2 Hematology
Hematology samples will be collected at Screening and at subsequent time points specified in 
Table 7-1.
Hematology parameters assessed are listed in Table 7-3.
7.2.2.6.3 Clinical chemistry
Clinical chemistry samples will be collected at Screening and at subsequent time points as 
specified in Table 7-1.
Clinical chemistry parameters assessed are listed in Table 7-3.
In accordance with the deferasirox label, serum creatinine, creatinine clearance, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, direct (conjugated) bilirubin, indirect bilirubin, total 
bilirubin must be assessed in duplicate before the initiation of therapy to establish a reliable 
pre-treatment baseline.
FRANCE SPECIFIC ONLY: Serum creatinine and creatinine clearance should be assessed 
at weeks 2 and 4 after initiation of deferasirox FCT as central lab tests. For patients enrolled 
in sites in France, serum creatinine and creatinine clearance will also be assessed at weeks 1 
and 3 after initiation of deferasirox FCT, and weekly during the first month after dose 
increases. The assessment is to be performed by the central lab however the local lab may be 
used. In the clinical database, “Unplanned Central Lab Cover Page” should be used to enter 
these unscheduled samples information at ‘Unplanned’ visit, or “Biochemistry Local 
Unplanned page” will be used in case of local lab assessment. The CRA will obtain the local 
laboratory reference ranges and a copy of the laboratory certification
Creatinine clearance will be calculated using the Cockcroft-Gault formula every time serum 
creatinine is collected.
7.2.2.6.4 Urinalysis
Urinalysis samples will be collected at Screening and at subsequent time points specified in 
Table 7-1.
Urinalysis parameters assessed are listed in Table 7-3.


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Macroscopic urinalysis will be performed by the site (dipstick supplied by the central lab).
Microscopic urinalysis will be performed by the central lab if the urine dipstick is positive. 
During screening, a non-first void morning urine sample (at least 15 ml) will be collected for 
a urinary protein/creatinine ratio (UPCR) to be assessed by the central lab for eligibility.
For patients who develop proteinuria or worsening pre-existing proteinuria (assessed by 
dipstick or central lab) at any visit, refer to Table 6-2.
7.2.2.6.5 Hepatitis tests
Hepatitis tests include hepatitis B surface antigen and antibody (HbsAg & HbsAb), hepatitis B 
core antibody (HbcAb), hepatitis C antibody (Anti-HCV), HCV PCR (Quantitative). Hepatitis 
testing will be conducted at the first Screening Visit to assess trial eligibility.
7.2.2.6.6 Coagulation
International normalized ratio (INR) will be measured at all screening visits and all visits 
during study treatment.
7.2.2.6.7 Transferrin saturation
Transferrin saturation (fasting) will be measured at all screening visits and all visits during 
study treatment.
7.2.2.6.8 Pregnancy and assessments of fertility
Serum and/or urine pregnancy tests will be performed for all females of child-bearing 
potential, according to the schedule in Table 7-1. 
A urine pregnancy test will be at Day 1, EOT and at the investigator’s discretion during the 
treatment period, as per Novartis guidelines for pregnancy testing in clinical trials when basic 
contraception is requested. 
See Section 8.4 for pregnancy reporting and follow-up requirements.
7.2.2.7
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed locally approximately every 6 months (Screening, 
Weeks 24, 52, 76, and 104).
Additional unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG eCRF. Each ECG tracing should be labeled with the study number, patient initials 


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(where regulations permit), patient number, and 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. Clinically significant findings must be discussed with Novartis prior 
to enrolling the patient. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the AE eCRFs.
7.2.2.8
Other assessment
Cirrhosis assessment will be performed locally unless diagnosis is available during the past 12 
months, or SF is <1000 μg/L and AST/ALT are normal.  The patient and physician have the 
option to choose an available test, e.g. liver biopsy, elastography ultrasound or radiologic 
exams, for cirrhosis assessment during screening, preferably at the first screening visit.
7.2.3
Pharmacokinetics
Not applicable
7.2.4
Biomarkers
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 (AEs)
8.1.1
Definitions and reporting
An AE is defined as the appearance (or worsening of any pre-existing) of undesirable sign(s), 
symptom(s), or medical condition(s) that occur after ICF has been signed.
Abnormal laboratory values or test results occurring after informed consent constitute an AE 
if they induce clinical signs or symptoms considered clinically significant, require therapy 
(e.g., hematologic abnormality that requires transfusion or stem cell support), or require 
changes in study medication.
Onset or worsening of AEs after informed consent should be recorded in the AE eCRFs. 
Conditions present at the time of informed consent should be recorded in the Medical History 
page of the eCRF. AE monitoring should be continued for at least 30 days (or 5 half-lives, 
whichever is longer) following the last dose of study treatment. AEs (including lab 


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abnormalities that constitute AEs) should be described with a diagnosis, 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 or not to an AE) will be collected through a Death form.
Detection of AEs should be sought by non-directed questioning of the patient during 
screening (after signing the ICF) and at each visit. AEs may also be volunteered by the patient 
during Screening, between visits, by physical examination, laboratory test, or other 
assessments. Each AE must be evaluated for:
1. Severity grade (mild, moderate, severe)
2. Duration (Start and end dates)
3. Relationship to study treatment (Reasonable possibility that AE is related: No or Yes)
4. Action taken with respect to study drug (None, Dose adjusted, Temporarily interrupted, 
Permanently discontinued, Unknown, or Not applicable)
5. Concomitant medication or therapy given (No concomitant medication/non-drug therapy; 
if Yes, provide the concomitant medication/non-drug therapy)
6. Seriousness criteria was met or not for an AE, as defined in Section 8.2.1
7. Outcome (Not recovered/not resolved, Recovered/resolved, Recovering/resolving, 
Recovered/resolved with sequelae, Fatal, Unknown)
For SAEs only, if there is improvement to a lower grade or worsening in toxicity, a new 
second entry with the start date should be reported in the eCRF.   
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the AE eCRF.
AEs must be followed until its resolution or until it is judged to be permanent. Assessment 
must be made at each visit (or more frequently, if necessary) of any change in severity, the 
suspected relationship to the study treatment, interventions required, and the outcome.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an AE (clinically significant, induce clinical signs or 
symptoms, require concomitant therapy or require a change in study treatment), should be 
recorded on the AE eCRFs. Whenever possible, a diagnosis, rather than a symptom, should be 
provided (e.g. anemia instead of low hemoglobin). They must be followed until resolved 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.


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Laboratory abnormalities, that do not meet the definition of an AE, should not be reported as 
AEs. A severe event does not automatically indicate an SAE unless it meets the definition of 
serious as defined below and/or as per investigator’s discretion. A dose hold or medication for 
the lab abnormality may be required by the protocol in which case the lab abnormality would 
still, by definition, be an AE and must be reported as such.
8.1.3
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are 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 (through 
timely reporting in the clinical database) may be appropriate. Such events may require further 
investigation in order to characterize and understand them. 
AESI are defined on the basis of an ongoing review of the safety data. AESI are discussed in 
detail in the Investigator Brochure. 
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

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:  hospitalizations for the following should not be reported as SAE:

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 unrelated to the 
indication under study and has not worsened since signing the ICF

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note:  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 SAE.


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8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided ICF and until at least 30 days after the patient has stopped study 
treatment, must be reported to Novartis within 24 hours of learning of its occurrence.
Any additional information for the SAE, including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one, 
should be reported separately as a new event.
Any SAEs experienced after the 30-day safety follow-up (or 5 half-lives, if half-life is 
established, whichever is longer) should be reported to Novartis only if the investigator 
suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the SAE 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
Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not, and whether the patient continued or withdrew from study 
participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Chief Medical Office and Patient Safety (CMO&PS) department associate may 
urgently require additional information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN) to inform all investigators 
involved in any study with the same drug that this SAE was reported. Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per 
national regulatory requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable, this is an open-label treatment study.


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8.4
Pregnancies
Serum and urine pregnancy tests will be performed for all females of child-bearing potential 
according to the schedule in Table 7-1. Urine pregnancy tests will also be performed at the 
investigator’s discretion during the treatment phase per Novartis guidelines for pregnancy 
testing in clinical trials when basic contraception is requested
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy must be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the 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 at the time of the approval of this study protocol indicated that special warnings 
or precautions were appropriate, other than those in the provided Investigator Brochure. 
Additional safety information collected between IB updates will be communicated in the form 
of Investigator Notifications and included in the ICF, which must be discussed with the 
patient.
8.6
Data Monitoring Committee
Not applicable
8.7
Steering Committee
The Steering Committee (SC) will be comprised of external experts in hematology, 
hepatology and ophthalmology who may be investigators participating in the trial and 
Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study, according to the protocol, by 
recommending and approving modifications as circumstances require per SC charter. The SC 
will also review protocol amendments as appropriate. Together with the clinical trial team, the 
SC will also develop recommendations for publications of study results, including authorship 
rules. Details of the role of the Steering Committee will be defined in a Steering Committee 
charter.


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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 revoked authorization to collect or use PHI, attempts will be 
made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering sensitive key personal identification information 
 
 the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, a field monitor will regularly visit the site to check the 
completeness of patient records, accuracy of entries on the eCRFs, adherence to the protocol 
according to Good Clinical Practice, progress of enrollment, and ensure that study drug is 
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 


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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 ICF (a signed copy is given 
to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
This study uses Electronic Data Capture (EDC). The eCRFs use validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements. Designated site staff will be given 
access to the EDC system after they are trained and will enter the data required by the 
protocol into the Electronic Case Report Forms (eCRF). Automatic validation programs check 
for data discrepancies in the eCRFs and allow modification or verification of the entered data 
by the investigator staff. The Investigator must certify that the data entered into the electronic 
Case Report Forms are complete and accurate and that entry and updates are performed in a 
timely manner.
9.4
Database management and quality control
Data entered by investigational staff will be reviewed by Novartis personnel (or designated 
CRO) for completeness and accuracy. Electronic data queries stating the nature of the 
problem and requests for clarification for discrepancies and missing values will be sent to the 
investigational site via the EDC system. Designated investigator site staffs are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and AEs will be coded using 
the Medical dictionary for regulatory activities (MedDRA) terminology.
Samples for central lab and photographs for central reading will be processed centrally and 
the results will be sent electronically to Novartis.
Randomization codes and data for all study drug dispensed to the patient and all IRT-assigned 
dosage changes will be tracked. The IRT system will also manage the database. The data will 
be sent electronically to Novartis.
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked. Authorization is required prior to making any database changes to locked 


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data, by joint written agreement between the Global Head of Biostatistics and Data 
Management and the Global Head of Clinical Development.
After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
10
Statistical methods and data analysis
Primary safety and efficacy analysis will be conducted on all patient data after final database 
lock.
10.1
Analysis sets
The following analysis sets will be used.
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment they have been assigned to during the randomization procedure.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of study treatment or 
phlebotomy. Patients will be analyzed according to the study treatment received, where 
treatment received is defined as the randomized treatment if the patient took that treatment (at 
least one dose or phlebotomy) or the first treatment received if the randomized treatment was 
never received.
10.1.3
Per Protocol Analysis Set:
Not applicable
10.1.4
Pharmacokinetic analysis set
Not applicable
10.1.5
Other analysis sets
Not applicable
10.1.5.1 Efficacy/evaluable set
Not applicable 


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10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data, including disease characteristics, will be listed and 
summarized descriptively by treatment group for the FAS and the Safety Set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
For selected parameters, 25th and 75th percentiles will also be presented when applicable.
Relevant medical histories and current medical condition at baseline will be summarized 
separately by system organ class (SOC) and preferred term (PT) for each treatment group. 
Ophthalmic history and phlebotomy history will also be summarized and listed for each 
treatment group using FAS.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented, as appropriate. 
For deferasirox, the duration of exposure in months and in categories (<3 months, 3-<6 
months, 6-<12 months, 12-<18 months and >18 months); as well as average planned dose, 
actual daily doses (mg/kg/day) and percentage of planned dose taken (ratio of cumulative 
actual on cumulative planned dose) will be summarized using descriptive statistics. The 
number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group; all dosing data will 
be listed.
For phlebotomy, summary statistics will be provided for the volume of blood removed and the 
frequency. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized by treatment group, according to the 
Anatomical Therapeutic Chemical classification system.
10.4
Primary objective
Assess the response rate (RR) of deferasirox FCT and phlebotomy treatment arms where 
response is defined by achieving target SF ≤ 100 μg/L on or before 24 months.  Estimate of 
the RR and corresponding 95% CI will be provided for each arm. No formal hypothesis 
testing is planned in this study.
10.4.1
Variable
The primary endpoint is the response rate by month 24, i.e. the proportion of patients whose 
SF ≤ 100 μg/L at any time on or before month 24.


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10.4.2
Statistical hypothesis, model, and method of analysis
The 2-sided 95% confidence interval will be constructed for the response rate by treatment 
arm based on the exact binomial distribution (Clopper-Pearson method).
10.4.3
Handling of missing values/censoring/discontinuations
For the primary analysis, patients are considered responders if they meet response criteria for 
the primary endpoint on or before month 24. Any patient who discontinues prematurely 
before meeting such criterion will be considered a non-responder.
10.4.4
Supportive and Sensitivity analyses
Not applicable
10.5
Secondary objectives
10.5.1
Key secondary objective
The key secondary objective for this study is to evaluate the ocular safety of deferasirox FCT 
and phlebotomy over 24 months. 
To characterize long-term ocular safety, the incidence of treatment-emergent ocular AEs (new 
or worsening from baseline) will be summarized categorically by system organ class and/or 
preferred term, overall and by severity, type of AE, and relation to study treatment. Ocular 
AEs will be defined in the study Statistical Analysis Plan (SAP).
Treatment-emergent AEs are defined as AEs started during on-treatment period: from the day 
of the first dose of study medication or the first phlebotomy to 30 days after the last dose of 
study medication or last phlebotomy.
No hypothesis will be tested for this key secondary objective.
10.5.2
Secondary efficacy objective(s)
The secondary efficacy objective is time to first response of achieving SF ≤100 μg/L. For this 
analysis, the following censoring rule will be applied:
For patients who did not achieve a response, they will be censored at the earliest of the 
following dates: 

Death or discontinuation date due to any reason

Last SF assessment.
Kaplan-Meier estimates will be presented. Median time to response (as well as 25th and 75th
percentiles) will be presented along with 95% confidence intervals for the two arms. 


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10.5.3
Secondary safety objectives
Secondary safety objectives include:

Safety and tolerability of deferasirox FCT and phlebotomy over 24 months

Change from baseline in visual acuity (ETDRS), intra-ocular pressure, retina or/and optic 
nerve abnormalities, and lens abnormalities at months 6, 12, 18, and 24.

Safety and tolerability of deferasirox FCT in patients who interrupt due to SF ≤ 100 μg/L 
and re-initiate therapy when > 300 μg/L.
See Section 3 for details on safety objectives.  Descriptive statistics will be provided for all 
safety objectives using the Safety set.
Safety and tolerability between deferasirox FCT and phlebotomy during 24 months of study 
period will be assessed through the incidence of new or worsening AEs, abnormal and 
clinically significant laboratory findings, and other abnormal safety findings. See Section 
10.5.3.2, Section 10.5.3.3, and Section 10.5.3.4 for details.
To assess the effect of deferasirox FCT and phlebotomy, the change from baseline in visual 
acuity (ETDRS), intra-ocular pressure, retina or/and optic nerve abnormalities, and lens 
abnormalities will be summarized descriptively by treatment and by visit. The detailed 
analysis will be detailed in the SAP. 
Incidence of AEs in patients who interrupted deferasirox FCT at least once due to SF ≤ 100 
μg/L and re-initiated ≥ 300 μg/L will be tabulated and listed. The detailed analysis will be 
detailed in the SAP. 
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period:  from the day of a patient’s informed consent to the day before the 
first dose of study medication or first phlebotomy
2. On-treatment period:  from the day of the first dose of study medication to 30 days after 
the last dose of study medication or last phlebotomy
3. Post-treatment period: starting at day 30+1 after last dose of study medication or last 
phlebotomy.
10.5.3.2 Adverse events (AEs)
Summary tables for AEs will include only AEs that started or worsened during the on-
treatment period, the treatment-emergent AEs. 


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The incidence of all treatment-emergent AEs (new or worsening from baseline) in both arms 
will be summarized by SOC and/or PT, severity, type of AE, relation to study treatment. 
CTCAE grade will not be used. 
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and SAEs (including those from the pre and post-treatment periods) will be 
listed and those collected during the pre-treatment and post-treatment period will be flagged.
Project-specific AESI are defined in the case retrieval strategy (CRS) with regular updates 
whenever necessary. 
Specific groupings of AESI will be considered, and the number of patients with at least one 
event in each grouping will be reported. Such groups consist of AEs for which there is a
specific clinical interest in connection with deferasirox. Certain AEs may be reported within 
multiple groupings/AESI.
AESI are defined by MedDRA terms. 
SAEs, non-SAEs and AESI during the on-treatment period will be tabulated. 
10.5.3.3 Laboratory abnormalities
All laboratory values will be converted into SI units and reported by the severity grade, using 
low/normal/high classifications based on laboratory normal ranges, and by notable/extended 
ranges for selected parameters (see Table 10-1).
Table 10-1
Criteria for clinically notable and extended notable laboratory ranges
Parameter
Criteria
Absolute neutrophils
< 1.5×109/L (extended range < 0.5×109/L)
Platelets
< 100×109/L (extended range < 50×109/L)
Hemoglobin
< 100 g/L
ALT and AST
> 5× ULN and > 2× baseline (extended range > 10× ULN and > 2× 
baseline)
Total bilirubin
> 2 mg/dL  
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)
Urinary protein/creatinine ratio
≥ 1.0 mg/mg at 2 consecutive measurements at least 7 days apart
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


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
Listing of all laboratory data with values flagged to show the corresponding 
normal/notable/extended ranges (see Table 10-1 above).
10.5.3.4 Other safety data
Data from ECG and auditory examinations will be listed and summarized separately with 
descriptive statistics as appropriate for the Safety set. All new or worsened abnormalities will 
be recorded as AEs. 
Vital signs 
The change from baseline in systolic and diastolic blood pressures, pulse rate, temperature 
and weight will be summarized by scheduled visit with n, mean, SD, minimum, median, and 
maximum values.
A listing will be provided for all vital signs and weight. Notable values will be flagged, 
according to criteria 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 ≥ 20 
mmHg
Diastolic blood pressure
≥ 105 mmHg / ≤ 50 mmHg with increase / decrease from baseline ≥ 15 
mmHg
Pulse rate
≥ 120 bpm / ≤ 50 bpm with increase / decrease from baseline ≥15 bpm
Weight
≥ 10% increase
10.5.3.5 Supportive analyses for secondary objectives
Not applicable
10.5.3.6 Tolerability
Not applicable
10.5.4
Pharmacokinetics
Not applicable
10.5.4.1 Data handling principles
Not applicable
10.5.5
Biomarkers
Not applicable


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10.5.6
Resource utilization 
Not applicable
10.5.7
Patient-reported outcomes
Not applicable
10.6
Exploratory objectives
Not applicable
10.7
Interim analysis
Not applicable
10.8
Sample size calculation
The primary objective of the study is to estimate response rates and therefore the sample size 
is not based on power calculations. Sample size calculations were performed for the 
deferasirox FCT and phlebotomy arms to estimate the response rate (RR) with reasonable 
accuracy (half-width of 95% confidence interval). 
Based on the Exjade study ICL670A2202, the patient dropout rate at month 6 (core study) is 
24% and 12% at month 12 (optional extension phase). Assuming decreasing dropout rate over 
time and expected better patient compliance with deferasirox FCT formulation, a sample size 
of 100 patients in the FCT arm is expected to have at least 60 patients followed for 24 months 
to fulfil the FDA post-marketing requirement with regard to the ocular toxicity assessment in 
patients receiving deferasirox. 
With a sample size of 100 on deferasirox FCT and 50 patients on phlebotomy, the projected 
half-widths of the 2-sided 95% confidence interval assuming various response rates are 
displayed in Table 10-3. The 95% confidence interval half-width extends at most to 0.096 and 
0.136 in the deferasirox FCT and phlebotomy arms, respectively.
Table 10-3
Half-width of 95% CI of response rates in deferasirox FCT and 
phlebotomy arms
Response rate (RR)
Half-width of the 95% CI for 
deferasirox FCT 
N=100
Half-width of the 95% CI for 
phlebotomy 
N=50
0.60
0.096
0.136
0.65
0.093
0.132
0.70
0.090
0.127
0.75
0.085
0.120
0.80
0.078
0.111
0.85
0.070
0.099
0.90
0.059
0.083


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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 and will 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 ICF must be reviewed and approved by a properly constituted 
Institutional 
Review 
Board/Independent 
Ethics 
Committee/Research 
Ethics 
Board 
(IRB/IEC/REB) before starting the study. In addition, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to 
provide 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
After providing written (witnessed, where required by law or regulation) IRB/IEC/REB-
approved informed consent, eligible patients may be included in the study. The patient should 
indicate assent by personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any 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 obtained must be 
captured in the eCRF.
In a separate document, Novartis will provide investigators a proposed ICF that is considered 
appropriate for this study and complies with the ICH GCP guideline and regulatory 
requirements. Any changes suggested by the investigator must be agreed to by Novartis 
before ICF is submitted to the IRB/IEC/REB, and a copy of the approved version must be 
provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child-bearing potential must be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy occurs during the study. In order to 
participate, 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 must not enter in the study.


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Protocol No. CICL670F2203
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. ...clinicaltrials.gov, before starting the 
study. In addition, results of interventional clinical trials in adult patients are posted 
on ...novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1-year of study completion (i.e., LPLV). 
Novartis follows the ICMJE authorship guidelines (....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 at poster or oral sessions 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 ....novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Every 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.


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Source data are 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 Principal Investigator. The eCRF is the primary data collection instrument. 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 eCRFs an audit trail will be maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Novartis provides written 
permission to dispose of them or requires their retention for additional 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 
name in any documents submitted to Novartis. Signed ICFs 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.


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Protocol No. CICL670F2203
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 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. 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. CICL670F2203
13
References (available upon request)
Bacon BR, Adams PC, Kowdley KV, et al. (2011) Diagnosis and management of 
hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver 
Diseases. Hepatology; 54:328
Bacon BR. (1997) Diagnosis and management of hemochromatosis. Gastroenterology; 
113:995. 
Beaton MD, Adams PC. (2007) The myths and realities of hemochromatosis. Can J 
Gastroenterol; 21(2):101-104.
Cançado R, Melo MR, de Moraes Bastos R, et al. (2015) Deferasirox in patients with iron 
overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study. Eur J 
Haematol. 95(6): 545-50. 
Cappellini MD, Cohen A, Piga A, et al. (2006) A phase 3 study of deferasirox (ICL670), a 
once-daily oral iron chelator, in patients with beta-thalassemia. Blood; 107(9):3455-62. 
European Association For The Study Of The Liver. (2010) EASL clinical practice guidelines 
for HFE hemochromatosis. J Hepatol; 53(1):3-22. 
Hanson EH, Imperatore G, Burke W. (2001) HFE gene and hereditary hemochromatosis: a 
HuGE review. Human Genome Epidemiology. Am J Epidemiol; 154:193.
Niederau C, Fischer R, Pürschel A, et al. (1996) Long-term survival in patients with
hereditary hemochromatosis. Gastroenterology; 110:1107. 
Morrison ED, Brandhagen DJ, Phatak PD, et al. (2003) Serum ferritin level predicts advanced 
hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med; 
138:627. 
Phatak P, Brissot P, Wurster M, et al. (2010) A phase 1/2, dose-escalation trial of deferasirox 
for the treatment of iron overload in HFE-related hereditary hemochromatosis.  Hepatology; 
52(5):1671-779.
Tavill AS, (2001) American Association for the Study of Liver Diseases, American College 
of Gastroenterology, American Gastroenterological Association. Diagnosis and management 
of hemochromatosis. Hepatology; 33:1321.
Vichinsky E. (2008) Clinical application of deferasirox: Practical patient management. Am J 
Hematology;83(5): 398–402.


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Protocol No. CICL670F2203
14
Appendices
14.1
Dosing tables (Deferasirox FCT)
For each patient the investigator and/or pharmacist will calculate a target daily dose taking 
into account patient’s body weight. When the calculated dose cannot be reached with the 
deferasirox FCT strengths available, the closest daily dose available will be prescribed. 
The following dosing table provides an efficient combination of tablet strengths reaching a 
certain daily dose for each body weight range.
These dosing tables have been constructed for each dosing group using lower and upper body 
weight limits of 35 and 140 kg, respectively. This is taking into account that the study will 
enroll male or female adults.
Table 14-1
Dosing table for 3.5 mg/kg/day of Deferasirox FCT
Pt Weight in Kg
Closest Dose
90 mg
180 mg
360 mg
35 - 38
90 mg
1
-
-
39 - 64
180 mg 
-
1
-
65 - 90
270 mg
1
1
-
91 - 115
360 mg
-
-
1
116 - 140
450 mg
1
-
1
Table 14-2
Dosing table for 7 mg/kg/day of Deferasirox FCT
Pt Weight in Kg
Closest Dose
90 mg
180 mg
360 mg
35 - 45
270 mg
1
1
-
46 - 57
360 mg
-
-
1
58 - 70
450 mg
1
-
1
71 - 83
540 mg
-
1
1
84 - 96
630 mg
1
1
1
97 - 109
720 mg
-
-
2
110 - 122
810 mg
1
-
2
123 - 135
900 mg
-
1
2
136 - 140
990 mg
1
1
2


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Table 14-3
Dosing table for 10.5 mg/kg/day of Deferasirox FCT
Pt Weight in Kg
Closest Dose
90 mg
180 mg
360 mg
35 - 38
360 mg
-
-
1
39 - 47
450 mg
1
-
1
48 - 55
540 mg
-
1
1
56 - 64
630 mg
1
1
1
65 - 72
720 mg
-
-
2
73 - 81
810 mg
1
-
2
82 - 90
900 mg
-
1
2
91 - 98
990 mg
1
1
2
99 - 107
1080 mg
-
-
3
108 - 115
1170 mg
1
-
3
116 - 124
1260 mg
-
1
3
125 - 132
1350 mg
1
1
3
133 - 140
1440 mg
-
-
4
Table 14-4
Dosing table for 14 mg/kg/day of Deferasirox FCT
Pt Weight in Kg
Closest Dose
90 mg
180 mg
360 mg
35
450 mg
1
-
1
36 - 41
540 mg
-
1
1
42 - 48
630 mg
1
1
1
49 - 54
720 mg
-
-
2
55 - 61
810 mg
1
-
2
62 - 67
900 mg
-
1
2
68 - 73
990 mg
1
1
2
74 - 80
1080 mg
-
-
3
81 - 86
1170 mg
1
-
3
87 - 93
1260 mg
-
1
3
94 - 99
1350 mg
1
1
3
100 - 106
1440 mg
-
-
4
107 - 112
1530 mg
1
-
4
113 - 118
1620 mg
-
1
4
119 - 125
1710 mg
1
1
4
126 - 131
1800 mg
-
-
5
132 - 138
1890 mg
1
-
5
139 - 140
1980 mg
-
1
5


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Protocol No. CICL670F2203
14.2
Examples of light meal
Example 1:
amount
kcal
g total fats
Wheat Bread or Toast
2 slices
138
2
jams, preserves, all flavors
1 Tablespoon
109
0
banana
medium (7-7 7/8" long)
105
0
orange juice
1 cup
114
0
skim milk
1 cup
83
0
Total:
549
2
Example 2:
amount
kcal
g total fats
Pita Bread 
1 medium (5.25" across) pita 
124
1
hummus or deli chicken/turkey
1 Tablespoon hummus or 2 oz. 
meat
27
1
apple
medium (2.75" across)
72
0
salsa, red, cooked
6 Tablespoons
26
0
carrots & celery sticks
4 carrot sticks (3" long) and small 
5" stalk of celery
14
0
Total:
263-295
2
Example 3:
amount
kcal
g total fats
yogurt, fruit, low-fat
6 oz.
173
2
banana
medium (7-7 7/8" long)
105
0
orange juice
1 cup
114
0
skim milk
1 cup
83
0
Total:
475
2
Example 4:
amount
kcal
g total fats
vegetable chicken noodle soup, 
canned
1 cup
70
2
baked potato, peel not eaten
1 medium (2.25-3" across)
121
0
skim milk
1 cup
83
0
banana
medium (7-7 7/8" long)
105
0
Total:
379
2


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Protocol No. CICL670F2203
Example 5:
amount
kcal
g total fats
egg whites, cooked, no fat added
2 large egg whites
32
0
salsa, red, cooked
6 Tablespoons
26
0
Wheat Bread or Toast
2 slices
138
2
jams, preserves, all flavors
1 Tablespoon
109
0
orange juice
1 cup
114
0
skim milk
1 cup
83
0
Total:
502
2
Example 6:
amount
kcal
g total fats
chicken, boneless, skinless 
baked
0.5 cup diced
111
2
salsa, red, cooked
6 Tablespoons
26
0
white rice, cooked, no fat added
0.5 cup
102
0
black beans, canned or cooked 
from dry, no fat added
0.5 cup
99
0
skim milk
1 cup
83
0
Total:
421
2

SAP_001.pdf: 
Clinical Development
ICL670/deferasirox/Exjade®
CICL670F2203 / NCT03203850
A phase II, multicenter, open-label, randomized two-year study to 
evaluate the efficacy and safety of deferasirox film-coated tablet 
versus phlebotomy in patients with Hereditary Hemochromatosis
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation
Document status:
Final Amendment 1
Release date:
22-May-2023
Number of pages:
36
Property of Novartis
For business use only
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Page 2 of 36
SAP Amendment 1
Study No. CICL670F2203
Document History – Changes compared to previous final version of SAP
Date
Time Point
Reason for 
update
Changes
Section and title 
impacted (Current)
21-Dec-2017
Prior to DB 
lock
Creation of 
final version 
N/A – First 
Version
NA
18-May-2023
Prior to DB 
lock
Creation of 
amendment 1
SAP was updated 
to reflect the 
latest changes as 
per the SAP 
template version 
6.
all
Creation of 
amendment 1
Addition of 
location of the 
SAP in CREDI
Section 1 -
Introduction
Creation of 
amendment 1
Addition of 
purpose of the 
study and HA 
commitment
Section 1.1 – Study 
design
Creation of 
amendment 1
Ocular 
assessment was 
included in the 
safety evaluation.
Section 2.1.1-
General definitions. 
Creation of 
amendment 1
Addition of 
definition of 
average actual 
daily dose, 
average planned 
daily dose; 
Clarification 
of 
definition 
of 
cumulative dose 
were added;
Addition of new 
definition of dose 
change; 
dose 
reduction; 
dose 
increase.
Section 2.3.1-Study 
treatment/compliance 


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SAP Amendment 1
Study No. CICL670F2203
Creation of 
amendment 1
Addition of box 
plot for serum 
ferritin
Section 2.4.2 –
Statistical 
hypothesis, model, 
and method of 
analysis
Creation of 
amendment 1
Removal of 
supportive 
analysis 
Section 2.4.4 –
Supportive analysis
Creation of 
amendment 1
Addition of 
treatment 
emergent 
definition.
Addition of clear 
categories 
of 
ocular AESI
Section 2.5.2 -
Statistical 
hypothesis, model, 
and method of 
analysis 
Creation of 
amendment 1
Following 
updates and 
clarifications 
added to for the 
of Ocular data 
analyses to 
address HA 
request: -
Clarification of 
definition of 
Ocular 
examinations; 
summary table ; 
additional of 
swimmers plot 
for key ocular 
assessment on 
treatment periods 
and post 
treatment 
periods;
Clarification 
of 
LogMAR 
conversion 
method 
and 
Section 2.6.2 –
Ocular examinations


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SAP Amendment 1
Study No. CICL670F2203
detailed analysis 
for Visual acuity ;
Addition of clear 
analysis of Slit 
lamp, 
summary 
table, shift table, 
listing 
for 
abnormalities, 
listing 
for 
MedDRA coded 
term.
Addition of clear 
analysis 
of 
Fundus 
Oculi, 
Table and listing 
for 
other 
abnormal 
findings 
MedDRA coded 
term;
Addition 
of 
analysis 
-
summary 
table 
and listing for the 
color 
fundus 
photography with 
and 
without 
abnormalities, 
Additional listing 
for 
findings; 
general 
comments 
and 
confidence score 
comments. 
Creation of 
amendment 1
Clear 
specification of 
AEs Analysis; 
summary tables 
Section 2.6.3 –
Adverse Event (AEs)


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Page 5 of 36
SAP Amendment 1
Study No. CICL670F2203
for different 
categories.
Addition 
of 
separate table of 
secondary safety 
objective on the 
evaluation 
of 
safety 
and 
tolerability 
of 
deferasirox FCT 
in subjects who 
interrupt to SF ≤ 
100 μg/L and re-
initiate 
therapy 
when ≥ 300 μg/L.
Additional 
analysis related to 
COVID-19 AEs.
Creation of 
amendment 1
clear 
specification of 
AESI Analysis, 
summary tables.
Section 2.6.5 -
Adverse Event of 
Special Interest 
(AESI)
Creation of 
amendment 1
Addition of 
disclosure related 
output
Section 2.6.6 –
Disclosure related 
outputs
Creation of 
amendment 1
Addition of 
descriptive 
statistics for the 
lab results.; 
redefinition of 
notable range for 
Hemoglobin, 
creatinine 
clearance.
Addition 
of 
conversion factor 
for 
the 
lab 
parameter 
–
urinary protein / 
creatinine 
ratio. 
Addition 
of 
summaries 
of 
Section 2.6.7 –
Laboratory data


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SAP Amendment 1
Study No. CICL670F2203
individual 
liver 
function 
parameters 
like 
ALT, AST etc.
Creation of 
amendment 1
redefinition of 
notable range 
vital sign(weight) 
Section 2.6.8 - Vital 
Signs and Weight
Creation of 
amendment 1
Addition of 
analysis related to 
COVID-19 AEs.
Section 4 – Change 
to protocol specified 
analyses
Creation of 
amendment 1
Addition of Date 
imputation for 
AE, LB, CM etc.
Section 5.1 –
Imputation rules
Creation of 
amendment 1
Update on End of 
treatment for 
Time windows 
for laboratory 
assessment
Section 5.3.1 –
Safety laboratory 
assessments
Creation of 
amendment 1
Addition of 
Ocular 
assessment 
analysis and 
window period 
Section 5.3.2 –
Ocular assessments
Creation of 
amendment 1
Addition of 
reference 
Section 6 - Reference


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SAP Amendment 1
Study No. CICL670F2203
Table of contents
Table of contents .................................................................................................................7
List of Abbreviations...........................................................................................................9
1
Introduction .......................................................................................................................10
1.1
Study Design..........................................................................................................10
1.2
Study Objectives and Endpoints............................................................................11
2
Statistical Methods ............................................................................................................11
2.1
Data Analysis General Information.......................................................................11
2.1.1
General Definitions...............................................................................12
2.2
Analysis sets ..........................................................................................................14
2.2.1
Subgroup of Interest..............................................................................15
2.3
Disposition, Demographics and Other Baseline Characteristics ...........................15
2.3.1
Subject Disposition ...............................................................................15
2.3.2
Demographics and Other Baseline Characteristics...............................16
2.4
Treatments (Study Treatment, Rescue Medication, Concomitant Therapies, 
Compliance)...........................................................................................................17
2.4.1
Study Treatment / Compliance..............................................................17
2.4.2
Prior and Concomitant Therapies..........................................................20
2.5
Analysis of the Supporting Primary Objective......................................................20
2.5.1
Primary Endpoint ..................................................................................21
2.5.2
Statistical Hypothesis, Model, and Method of Analysis.......................21
2.5.3
Handling of Missing Values/ Discontinuations ....................................21
2.6
Analysis Supporting Secondary Objectives...........................................................21
2.6.1
Key Secondary Endpoint.......................................................................21
2.6.2
Statistical Hypothesis, Model, and Method Of Analysis ......................21
2.7
Analysis of Secondary Efficacy Objective............................................................22
2.7.1
Secondary Efficacy Endpoint................................................................22
2.8
Secondary Safety Objectives.................................................................................22
2.8.1
Ocular Examinations.............................................................................23
2.8.2
Adverse Events (AEs)...........................................................................25
2.8.3
Deaths....................................................................................................27
2.8.4
Adverse Events of Special Interest (AESI)...........................................27
2.8.5
Disclosure Related Outputs...................................................................27
2.8.6
Laboratory Data ....................................................................................28
2.8.7
Vital Signs and Weight .........................................................................30
2.8.8
Other Safety Data..................................................................................30


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SAP Amendment 1
Study No. CICL670F2203
3
Sample Size Calculation....................................................................................................30
4
Change to protocol specified analyses ..............................................................................31
5
Appendix ...........................................................................................................................31
5.1
Imputation Rules....................................................................................................31
5.1.1
Study Treatment....................................................................................31
5.1.2
AE Date Imputation ..............................................................................32
5.1.3
Prior and Concomitant Medication Date Imputation............................32
5.1.4
Incomplete Date of Diagnosis of Hemochromatosis History ...............33
5.2
Laboratory Parameters Derivations .......................................................................33
5.2.1
Re-derived Creatinine Clearance ..........................................................33
5.2.2
Multiple Assessments Within Post-Baseline Visits..............................33
5.3
Time-Windows ......................................................................................................33
5.3.1
Safety Laboratory Assessments ............................................................33
5.3.2
Ocular Assessments ..............................................................................34
6
Reference...........................................................................................................................36


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Page 9 of 36
SAP Amendment 1
Study No. CICL670F2203
List of Abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ALP
Alkaline Phosphatase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
BCVA
Best Corrected Visual Acuity
CRS
Case Retrieval Sheet
CSR
Clinical Study report
ETDRS
Early Treatment Diabetic Retinopathy Study
FAS
Full Analysis Set
DAR
Dose Administration Record
DI
Dose Intensity
DRL
Drug Reference Listing
FCT
Film-Coated Tablet
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOT
End Of Treatment
EOS
End of study 
HGLT
High Level Group Term
HLT
High Level Term
IVR
Interactive Voice Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NMQ
Novartis MedDRA Queries
PDI
Planned Dose Intensity
PT 
Preferred Term
RDI
Relative Dose Intensity
RR
Response Rate
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SF
Serum Ferritin
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
TFLs
Tables, Figures, Listings
TBL
Total Bilirubin
TTR
Time To Response
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report 
(CSR) of study CICL670F2203, a phase II, multicenter, open-label, randomized two-year study 
to evaluate the efficacy and safety of deferasirox film-coated tablet versus phlebotomy in 
subjects with Hereditary Hemochromatosis. 
The content of this SAP is based on protocol CICL670F2203 version 01. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data.
The CSR SAP is located at the following CREDI location:
/CREDI Projects/I/ICL670F/CREDI Studies/ICL670F2203/Administrative Files (study 
level)/RAP or RAMP Meeting – CICL670F2203_SAP (Statistical Analysis Plan)
1.1
Study Design
This is a randomized, multicenter, open-label, two-year, Phase II study to evaluate the efficacy 
and safety of deferasirox Film-Coated Tablet (FCT) versus phlebotomy in subjects with 
Hereditary Hemochromatosis with iron overload. 
Eligible subjects will be identified during a 4-week screening period, then randomized to either 
deferasirox FCT or phlebotomy beginning on Day 1 and treated for 24 months (104 weeks). A 
total of 150 adults were planned to be randomized in a 2:1 ratio (100 subjects to deferasirox 
FCT and 50 subjects to phlebotomy). The present study is being conducted to fulfill post-
marketing requirements for EXJADE.
After end of treatment (EOT), there is a standard 30-day safety follow-up. If a subject
discontinues from treatment in either arm and has completed at least 6 months of assessments, 
they will be encouraged to continue in a Post-treatment Ocular Follow-up phase and undergo 
ocular exams every 6 months as scheduled to receive a total of at least 5 ophthalmological 
examinations. End of study (EOS) occurs after the last subject has completed last visit which 
includes a 30-day safety follow-up. This last subject may have either completed 24 months (104 
weeks) of treatment, or prematurely discontinued and completed ocular assessments. After 
completing the study or discontinuing from study treatment, subjects will receive standard of 
care.
The primary analysis will be conducted on all subjects’ data after final database lock. No interim 
analysis is planned.
The present study is being conducted to fulfill post-marketing commitments/ requirements for 
EXJADE PMC 750-10, NDA 021882) and JADENU (PMR 2888-8, NDA 206910).
 
 
 
 
 
 


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1.2
Study Objectives and Endpoints
The study objectives as outlined in the [protocol Section 3] are as follows (Table 1-1).
Table 1-1 Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to 
Assess the response rate in the 
deferasirox FCT and phlebotomy 
treatment arms where response is 
defined by achieving target SF ≤ 100 
μg/L on or before 24 months.
Proportion of Subjects achieving target 
SF ≤ 100 μg/L for the first time.
Section 2.5
Key Secondary
Refer to 
Characterize the ocular safety of 
deferasirox FCT and phlebotomy over 
24 months.
Incidence of ocular AEs overall and by 
severity, type of AE, and relation to 
study treatment.
Section 2.6
Secondary
Refer to 
Evaluate the safety and tolerability of 
deferasirox FCT and phlebotomy over 
24 months.
Incidence of AEs, AEs leading to 
discontinuation from study, laboratory 
abnormalities, and deaths.
Sections 2.8
Assess the change from baseline in 
visual acuity, intra-ocular pressure, 
retina or/and optic nerve abnormalities, 
and lens abnormalities at months 6, 12, 
18, and 24 of deferasirox FCT and 
phlebotomy.
Change from baseline at months 6, 12, 
18 and 24 in visual acuity, tonometry, 
slit lamp, and fundus exams.
Section 2.8.1
Assess the safety and tolerability of 
deferasirox FCT in subjects who 
interrupt and re-initiate treatment due to 
SF levels ≤ 100 μg/L and ≥ 300 μg/L.
Incidence of AEs in subjects who 
interrupt due to reaching target SF 
≤ 100 μg/L, then re-initiate therapy at 
≥ 300 μg/L.
Sections 2.8
Assess the first time to response 
(defined as SF ≤ 100 μg/L) between the 
deferasirox and phlebotomy treatment 
groups.
Time to reach target SF ≤ 100 μg/L in 
the deferasirox and phlebotomy arms 
for the first time.
Section 2.7
2
Statistical Methods
2.1
Data Analysis General Information
Data will be analyzed by Novartis Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis Section 10 of the study protocol as detailed in this 
analysis plan. 
SAS® version 9.4 (or later version if available at time of database lock) will be used to perform 
all data analyses and to generate tables, figures, and listings. 
Data Included in the Analysis
Data from all subjects who signed informed consent will be used in the analysis. All statistical 
analyses described hereafter will be performed using all data collected in the database up to the
final database lock date. The final database lock date will be established after all randomized


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subjects have completed 24 months of treatment including safety follow-up if applicable, or 
have discontinued from the study (see Protocol Section 4.3 for more details) . 
General Analysis Conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of subjects enrolled at centers, no center effect 
will be assessed.
Qualitative/categorical data (e.g., sex, race) will be summarized by frequency counts and 
percentages. Percentages will be calculated using the number of subjects in the relevant 
treatment arm as the denominator.
Continuous data (e.g., age, body weight) will be summarized using appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment arm.
Lower and upper quartiles will also be presented when applicable.
2.1.1
General Definitions 
Study Treatment
The term study treatment/treatment group will refer both to Deferasirox FCT (DFX) or 
Phlebotomy.
Date of First/Last Administration of Study Treatment 
For Deferasirox FCT:

The date of first administration of study treatment is derived as the first date when a 
non-zero actual dose of study treatment was administered as recorded on Dose
Administration Record (ZQ) Electronic Case Report Form (eCRF). 

The date of last administration of study treatment is defined as the last date when a non-
zero actual dose of study treatment was administered as recorded on ZQ eCRF. 
For Phlebotomy:

The date of first administration of study treatment is derived as the first date when a 
non-zero volume of blood removed was recorded on Phlebotomy Record eCRF (FAZU) 
on or after the randomization date. 

The date of last administration of study treatment is defined as the last date when a non-
zero volume removed of blood was recorded on Phlebotomy Record eCRF (FAZU). 
This date will also be referred as ‘last date of study treatment’.
Study Day
The study day for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, Electrocardiogram (ECG), Ocular, etc.) will be calculated 
using the start date of study treatment as the reference. For assessments occurring 


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
On or after the start date of study treatment, the study day will be calculated as (date of 
safety assessment) – (start date of study treatment) + 1. Study day 1 will therefore be the 
first day of study treatment.

Before the start date of study treatment, the study day will be calculated as (date of safety 
assessment) – (start date of study treatment). 
For example, if an adverse event starts 3 days before the start of study treatment the study day 
displayed on the listing will be negative, i.e. -3. 
The study day for efficacy assessments (i.e. serum ferritin) will be calculated using the 
randomization date as the reference. For assessments occurring

On or after randomization date, the study day will be calculated as (date of non-safety 
assessment) – (date of randomization) + 1. Then study day 1 will be the day of 
randomization. 

Before randomization date, the study day will be calculated as (date of non-safety 
assessment) – (date of randomization). 
The study day will be displayed in the data listings. 
Time Unit
A month length is 30.4375 days (365.25/12). If duration is reported in months, duration in days 
will be divided by 30.4375.
Baseline
Baseline is considered as the result of an investigation describing the ‘true’ uninfluenced state 
of the subject.
For efficacy evaluations, (e.g. serum ferritin), the last available assessment before or on the 
date of randomization is taken as ‘baseline’ value or ‘baseline’ assessment. 
For safety evaluations (e.g. laboratory, vital signs, ocular etc.) the last available assessment 
before or on the date of start of study treatment is taken as ‘baseline’ value or ‘baseline’ 
assessment.
If subjects have no value as defined above, the baseline result will be missing.
If an assessment is planned to be performed prior to the first administration of study treatment 
in the protocol and the assessment is performed on the same day as the first administration of 
study treatment, it will be assumed that it was performed prior to study treatment administration 
if assessment timepoint is not collected or is missing. Unscheduled assessments will be 
considered in the determination of baseline. 
Subjects who start treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study Day 1, one being reported to the Day 1 visit, the other 
reported to the EOT visit. Data reported at the EOT visit are not eligible for baseline selection.


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On-treatment Period
The overall observation period (for both Deferasirox and Phlebotomy) will be divided into three 
mutually exclusive segments:

Pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment;

On-treatment period: from day of first administration of study treatment to 30 days after 
last administration of study treatment;

Post-treatment period: starting at day 30+1 after last administration of study treatment to 
end of study.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). For additional details refer to specific section – Section 2.6.3 details on 
AEs and Section 5.3.2 on Ocular assessments.
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment they have been assigned to during the randomization procedure.
Safety Set
The Safety Set includes all subjects who received at least one administration of study treatment. 
Subjects will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized treatment if the subject took that treatment (at least one 
administration or phlebotomy) or the first treatment received if the randomized treatment was 
never received.
Screen Failures
Screen failures are subjects who have signed the informed consent and who failed to be 
randomized for any reason (i.e. failing to meet inclusion or exclusion criteria or any other 
screening procedure).
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a subject
withdraws full consent is recorded in the eCRF.
Death events may be used in the analysis if captured from public records (registers), local law 
and subject informed consent permitting.


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2.1.2
Subgroup of Interest
NA
2.2
Disposition, Demographics and Other Baseline Characteristics
The FAS will be used for all baseline and demographic summaries and listings, unless otherwise 
specified. Summaries will be reported by treatment arm and for all subjects and listings will be 
reported by treatment arm to assess baseline comparability. No inferential statistics will be 
provided.  
2.2.1
Subject Disposition
Enrollment by country and center will be summarized by treatment arm using the FAS. The 
number (%) of randomized subjects included in the FAS will be presented overall and by 
treatment group. The total number of screen failures will also be displayed in listings. The 
number (%) of subjects in the FAS who discontinued the study phases and the reason for 
discontinuation will be presented overall and by treatment group.
The following summaries will be provided (with % based on the total number of FAS subjects):

Number (%) of subjects who were randomized (based on data from IRT system)

Number (%) of subjects who were randomized but not treated (based on ‘ZQ’ & 
“FAZU” eCRF page)

Number (%) of subjects who were treated (based on ‘ZQ’ & “FAZU” eCRF pages 
of each study treatment component completed with non-zero dose administered)

Number (%) of subjects who discontinued the study treatment phase (based on the 
‘End of Treatment Phase’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘End of 
Treatment Phase’ page)

Number (%) of subjects who have entered the post-treatment follow-up (based on 
the ‘End of Treatment Phase’ page)

Number (%) of subjects who have discontinued from the post-treatment follow-up 
(based on the End of Post-treatment follow-up page)

Reasons for discontinuation from the post-treatment follow-up (based on End of 
Post-treatment follow-up page)
Listings will also be generated for the subject disposition.
Protocol Deviations
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan) overall and by treatment group 
for the FAS.
All protocol deviations will be listed based on FAS. Subjects with COVID-19 related protocol 
deviations will be presented separately in the table and listing for FAS by category and 
relationship.


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The full list of protocol deviations is documented in the Study Specification Document (SSD). 
The COVID-related protocol deviations and relationship to pandemic will be identified and 
maintained in an independent tracker located in the document management system in the 
“CREDI Studies/ICL670F2203/TMF (Study Level)/Protocol Deviations” folder. The latest 
available tracker prior to database lock will be used.
Analysis Sets
The number (%) of subjects in each analysis set (defined in Section 2.1.1) will be summarized
by treatment group.
2.2.2
Demographics and Other Baseline Characteristics
The FAS will be used for all subject demographic and baseline characteristic summaries and 
listings, unless otherwise specified.
Basic Demographic Data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups: 18 to <65 and ≥65 years, race, and 
ethnicity) will be summarized by frequency counts and percentages; the number and percentage 
of subjects with missing data will be provided. Continuous data (e.g. age and weight) will be 
summarized by descriptive statistics (N, mean, median, standard deviation, minimum and 
maximum). 
The number of subjects by sex and age categories and the number of subjects by race will be 
tabulated. 
Phlebotomy History
Summary statistics will be provided for the volume of blood removed (average of the volume 
removed per subject) and the frequency (number of procedures per subject) of phlebotomy 
procedure (based on records reported before the randomization date in ‘Phlebotomy Record’ 
page).
Average Volume Removed per subject = Sum of Volume removed/frequency
A listing will also be provided.
Medical History
Medical history and ongoing conditions entered on (e) CRF will be summarized and listed by 
treatment arm. Separate summaries will be presented for ongoing and historical medical 
conditions. The summaries will be presented by primary system organ class (SOC), preferred 
term (PT) and treatment arm. Medical history and current medical conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The MedDRA 
version used for reporting will be specified in the CSR and as a footnote in the applicable
tables/listings.
Ocular medical history and ongoing conditions will be summarized and listed by treatment arm. 


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Other Baseline Characteristics
Descriptive statistics, frequency counts and percentages will be tabulated by treatment arm, as 
appropriate for history of cirrhosis (yes or no), clinically significant abnormality in ECG (yes 
or no) and overall interpretation in audiometric test (normal or clinically significant or 
insignificant abnormality) on the Safety set. 
The Serum Ferritin at baseline will be summarized as both continuous (descriptive statistics) 
and categorical variable. It will be categorized as: <1000, ≥1000 to 2000, >2000 μg/L 
All data collected will be listed.
2.3
Treatments (Study Treatment, Rescue Medication, Concomitant
Therapies, Compliance)
The Safety Set will be used for medication data summaries and listings, unless otherwise 
specified.
2.3.1
Study Treatment / Compliance
Deferasirox FCT
Duration of exposure, daily dose, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment arm. Duration of exposure will be categorized 
into time intervals; frequency counts and percentages will be presented for the number (%) of 
subjects in each interval. The number (%) of subjects who have dose reductions, increases, or 
interruptions, and the reasons, will be summarized by treatment group. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.
The safety set will be used for all summaries and listings of study treatment. 
1. Duration of Exposure & Daily Dose

Duration of exposure to DFX FCT (days) = (date of last administration of study 
treatment) – (date of first administration of study treatment) + 1. 
Summary of duration of exposure of DFX FCT in appropriate time units will include categorical 
summaries based on <12, 12-<24, 24-<52, 52-<76 and >76 weeks and continuous summaries 
(i.e. mean, standard deviation etc.).

Average Actual Daily Dose (mg/kg/day) = Sum of all ((Dose X/current weight) * 
Corresponding duration of exposure on dose X) / overall duration of exposure

Average Planned Daily Dose (mg/kg/day) = Sum of all (Dose X * Corresponding 
duration of exposure on dose X) / overall duration of exposure
Average daily dose is the dose over all days between first and last dose, excluding
interruptions. The actual dose in mg/kg/day will be obtained by dividing the actual total 
daily dose administered in the DAR eCRF page by the last available weight at the time of 


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dose administration reported in the vital signs eCRF page. The planned dose in the eCRF is 
reported in mg/Kg unit, and therefore the dose is already adjusted for the subject weight 
when calculating the average planned daily dose.
2. Cumulative Dose
The planned daily dose of a subject is collected on the CRF page as dose prescribed in 
mg/kg/day and the actual daily dose is calculated by dividing the total daily dose collected on 
the CRF page in mg by the current weight (kg) corresponding to that visit. The current weight 
is equal to the weight on the same visit when dose had been administered or the last available 
weight before the dosing visit if the same visit weight is missing. Cumulative dose (mg/kg) is
defined as the sum over the daily doses of all days between first and last dose. 
Cumulative dose = sum of (daily dose at a visit * (end date of dose –start date of dose +1). 

The planned cumulative dose (mg/kg) for DFX FCT refers to the total planned dose 
as per the protocol up to the last administration of study treatment.

The actual cumulative dose (mg/kg) refers to the total actual dose administered, over 
the duration for which the subject is on the DFX FCT as documented in the Dose 
Administration eCRF. 
For subjects who did not take any drug the cumulative dose is by definition equal to zero.
The actual cumulative dose is the sum of the non-zero doses recorded over the dosing period 
and the planned cumulative dose is the planned starting dose summed over the same dosing 
period.
3. Dose Intensity and Relative Dose Intensity

Actual Dose Intensity (DI) for subjects with non-zero duration of exposure is defined 
as follows: 
DI (mg/kg/day) = Actual Cumulative dose (mg/kg) / Duration of exposure to DFX FCT 
(day).
For subjects who did not take any drug the DI is by definition equal to zero. The denominator 
for DI, i.e., duration of exposure includes days of 0 doses.

Planned Dose Intensity (PDI) is defined as follows:
PDI (mg/kg/day) = Planned Cumulative dose (mg/kg) / Duration of exposure to DFX 
FCT (day).

Relative Dose Intensity (RDI) is defined as follows:
RDI = [DI (mg/kg/day) / PDI (mg/kg/day)]*100.
The actual dose intensity and relative dose intensity will be summarized using descriptive 
statistics using the Safety Set. Additionally, categories of the RDI (<= 75%, >75% -90%, >90%-
110%, >110%) will be summarized through frequency and percentage. 
Dose Reduction/ Increases, Interruptions or Permanent Discontinuations


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The number of subjects who have dose reductions, increases, permanent discontinuations or 
interruptions, and the reasons, will be summarized separately for each of the study treatment 
components in the DFX arm only. 
‘Dose Changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the DAR
CRF pages will be used to determine the dose reductions, dose interruptions, and permanent 
discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘change in actual dose administered’ 
where the dose is different from previous visit (increase or decrease). For the purpose of 
summarizing interruptions and reasons; in case multiple entries for interruption that are entered 
on consecutive days with different reasons will be counted as separate interruptions. However, 
if the reason is the same in these mentioned multiple entries on consecutive days, then it will 
be counted as one interruption. 
Dose Reduction: When in the DAR CRF page, dose change  field is equal to ‘yes’ and the 
reason for dose change is present, then a dose reduction is considered if the non-zero actual 
daily dose administered (mg) , after weight adjustment in mg/kg, is lower (>15% ) than the 
previous non-zero actual daily dose administered (mg), and after weight adjustment in mg/kg 
(threshold of >15% is applied to the dose adjusted for weight in mg/kg, see below, received by 
the subject or if the non-zero actual daily dose administered (after weight adjustment in mg/kg) 
is lower (>15% ) than the dose amount based on the prescribed dose (mg/kg).
Dose Increases: When in the DAR CRF page, dose change field is equal to ‘yes’ and the reason 
for dose change is present, then a dose increase is considered if the non-zero actual daily dose 
administered (mg), after weight adjustment in mg/kg, is higher (>15% ) than the previous non-
zero actual daily dose administered (mg), and after weight adjustment in mg/kg (threshold 
of >15% is applied to the dose adjusted for weight in mg/kg, see below,  received by the subject 
or if the non-zero actual daily dose administered (after weight adjustment in mg/kg) is higher
(>15% ) than the dose amount based on the prescribed dose (mg/kg).
Any dose change to correct a dosing error will not be considered a dose reduction (subject goes 
back to previous prescribed/actual dose after a dose change due to dosing error) or a resumption 
of dose as per protocol after an interruption (subject goes back to previous prescribed/actual 
dose after a dose interruption as per protocol). The threshold of 15% is applied to the percentage 
change of dose calculated by (Dprevious-Dcurrent/Dprevious ) X 100. 
For example, due to weight adjustments when calculating actual dose differences between 
current and previous dose, 15% increment or decrement is checked when comparing current 
non-zero actual dose with previous non-zero actual dose when checking for dose resumption 
after an interruption as per protocol. 
Dose reductions/increases will be derived programmatically,
and number of dose 
reductions/increases will be reported.
Phlebotomy 


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Summary statistics will be provided for duration of exposure, average volume of blood (mL)
removed and average frequency of procedure by treatment arm.
For each subject, listing of each phlebotomy administered along with the volume removed and 
the hematocrit record will be produced. Any subjects from DFX FCT arm with Phlebotomy 
during post treatment follow up will be flagged.
2.3.2
Prior and Concomitant Therapies
Concomitant Medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject coinciding with the study treatment 
period. Concomitant therapy includes medications (other than study treatments) starting on or 
after the start date of study treatment or medications starting prior to the start date of study 
treatment and continuing after the start date of study treatment. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system and summarized by ATC level 2 and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing. The safety set will be used for all concomitant medication tables 
and listings.
Prior Therapies
Prior medication is defined to be drugs starting and ending prior to the first dose of study 
medication. The number and percentage of subjects who received any prior medications will 
be listed and summarized by treatment arm by lowest ATC class, preferred term, and treatment. 
The above analyses will be performed using the FAS.
2.4
Analysis of the Supporting Primary Objective
The primary objective of this study is to assess the response rate (RR) of deferasirox FCT and 
phlebotomy treatment arms where response is defined by achieving target Serum Ferritin (SF)
≤ 100 μg/L on or before month 24 (week 104).


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2.4.1
Primary Endpoint
The primary endpoint is the RR by month 24 (week 104) , i.e. the proportion of subjects whose 
SF ≤ 100 μg/L for the first time on or before month 24 (week 104) . All post-baseline SF values 
collected until week 104 (EOT) will be considered to derive the primary endpoint (including 
unscheduled and repeat measurements).
The primary analysis will be carried out in the FAS. 
2.4.2
Statistical Hypothesis, Model, and Method of Analysis
RR is defined as the proportion of subjects whose SF ≤ 100 μg/L at any time on or before month 
24 and the response rate will be summarized (proportion) by treatment arm along with two-
sided exact binomial 95% CIs [Clopper and Pearson 1934]. The analyses will be descriptive
only. No formal hypothesis testing is planned.
In addition, a box plot for serum ferritin by timepoint and treatment arm and line graph for 
individual subject values for serum ferritin by timepoint and treatment arm will be plotted. 
2.4.3
Handling of Missing Values/ Discontinuations
For the primary analysis, subjects are considered responders if they meet response criteria for
the primary endpoint on or before month 24 (week 104). Any subject who discontinues 
treatment prematurely before meeting such criterion is counted as non-responder. Any subjects 
with unknown or missing SF (no viable post-baseline SF assessment during the study) by 24 
months will also be counted as non-responder.
2.5
Analysis Supporting Secondary Objectives
The key secondary objective for this study is to characterize the ocular safety of deferasirox 
FCT and phlebotomy over 24 months. 
2.5.1
Key Secondary Endpoint
The key secondary endpoint is the Ocular Adverse Event as defined by AESI of “Lens disorders, 
retinal disorders and optic neuritis”. This analysis will be carried out in the Safety Set. 
2.5.2
Statistical Hypothesis, Model, and Method of Analysis
To characterize long-term ocular safety, the incidence of treatment-emergent ocular AEs (new
or worsening from baseline) will be summarized (along with two-sided exact binomial 95% CIs 
[Clopper and Pearson, 1934]) by preferred term, overall and by severity, type of AE (e.g. serious, 
leading to study drug discontinuation, requiring dose adjustment or/and interruption), and 
relation to study treatment.
Treatment-emergent AEs are defined as AEs started during on-treatment period: from the day 
of the first dose of study medication or the first phlebotomy to 30 days after the last dose of 
study medication or last phlebotomy.
All ocular AEs included under “Lens disorders, retinal disorders and optic neuritis” Adverse 
Event of Special Interest (AESI, listed in the compound case retrieval strategy) will be reported. 


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The above analysis will also be repeated for the overall period (on-treatment & post-treatment). 
The analyses will be descriptive. No formal hypothesis testing is planned for this key secondary 
objective. 
A listing of Ocular AEs will also be generated, and post-treatment events will be flagged.
2.6
Analysis of Secondary Efficacy Objective
The secondary efficacy objective is to assess the first time to response of achieving SF ≤ 100 
μg/L between the deferasirox and phlebotomy treatment arms. 
2.6.1
Secondary Efficacy Endpoint
The secondary efficacy endpoint of the study is the time from the date of randomization to the 
date of the first time the SF is achieving a value ≤ 100 μg/L on or before month 24 (week 104) , 
defined as Time To Response (TTR). This analysis will be carried out in the FAS. 
TTR (in months) will be listed and summarized by treatment arm. The distribution of time to 
response will be estimated using the Kaplan-Meier method and the median time to response 
will be presented along with 95% confidence interval only if a sufficient number of responses 
is observed. 
No inferential analysis that compares time to response between the two treatment arms will be 
performed.
Subjects who do not achieve SF ≤ 100 μg/L will be censored as follows:

at the last serum ferritin assessment date on or before month 24 (week 104),

at the day of randomization if a subject does not have any post-baseline serum ferritin value,

at the death date
Secondary Safety Objectives
Secondary safety objectives include:

Assessment of change from baseline in visual acuity, intra-ocular pressure, retina or/and 
optic nerve abnormalities, and lens abnormalities at months 6, 12, 18, and 24.

Evaluation of safety and tolerability of deferasirox FCT and phlebotomy over 24 months

Evaluation of safety and tolerability of deferasirox FCT in subjects who interrupt due to 
SF ≤ 100 μg/L and re-initiate therapy when ≥300 μg/L.
Unless otherwise specified, the following analyses will be performed by treatment arm on the 
Safety Set. All data, regardless of observation period, will be listed by treatment arm. Safety 
assessments starting during the pre-treatment or post-treatment period will be flagged in the 
listings. Safety assessments starting prior to study day 1 will appear with negative study day in 
the listings.


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2.6.2
Ocular Examinations
Each ocular examination will be analyzed by eye side and treatment arm separately for the 
overall (on-treatment and post-treatment) period. The frequency and percentage of subjects with 
completed ocular assessments will be presented by eye side, evaluation type, timepoint, and 
treatment arm. Additionally, a summary for the number of ocular examinations performed at 
each time point will be presented by treatment arm. Furthermore, swimmer plots for key ocular 
assessments of interest will be generated along with dosing information to delineate the ocular 
assessments which were on the on-treatment and post-treatment periods. See additional details 
in (Ocular Assessments Section 5.3.2)
Visual Acuity
The visual acuity will be measured using an Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart. A letter score is calculated based on the number of letters that can be correctly 
identified from specified distances. The ETDRS score entered into the CRF pages accounts for 
the distance at which the measurement was made (Section 1.1 of Manual of Ophthalmic 
Procedures for CICL670F2203); there will be no further adjustment while calculating logMAR. 
For low luminance and standard acuity measures, visual acuity will be described on a logMAR 
scale for all measures. For including acuity obtained with the ETDRS letters, the values will be 
converted to a logMAR scale, using the following formula (Beck et al, 2003):
logMAR = 1.7-0.02*ETDRS score,
where ETDRS score is the visual acuity ETDRS score. Finger counting, hand motion, and light 
perception will be assigned logMAR values of 2.0, 2.3, and 2.6 respectively (with a 0.3 logMAR 
increment per step). No light perception will be assigned a logMAR value of 2.9 (based on 
Lange et al, 2009).
The following shift tables will be generated using the categories (<0.1, ≥0.1 to <0.2, ≥0.2 to 
<0.3, ≥0.3 to <0.6, ≥0.6) by treatment group -

Comparing baseline and increases from baseline in logMAR score category at each 
visit by eye side (right & left )

Comparing baseline and decreases from baseline in logMAR score category at each 
visit by eye side (right & left)
Change from baseline (logMAR) = Post Baseline Value (logMAR) – Baseline Value
(LogMAR)
Swimmer plots will be generated to show the change in the categories of logMAR at baseline 
versus scheduled visits by treatment arm and eye side. The on- treatment period will also be 
displayed on the plot.
The number and percentage of subjects with the following change from baseline for logMAR 
categories (<0.1, ≥0.1 to <0.2, ≥0.2 to <0.3, ≥0.3 to <0.6, ≥0.6) will be summarized by treatment 
arm for the overall period -

the best change (decrease) in logMAR score category from baseline by eye side (right, 
left, best)


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
the worst change (increase) in logMAR score category from baseline by eye side (right, 
left, worst)
The changes from baseline at each visit will be calculated for assessments done in the same 
correction method as at baseline.
A listing with the ETDRS score, logMAR score abnormalities and change from baseline 
categories will be provided for all subjects.
Tonometry
Descriptive statistics for the intraocular pressure at baseline, at each post-baseline visit and 
changes from baseline at each post-baseline visit will be presented, by eye and treatment arm. 
Box plot for intraocular pressure by eye side and treatment arm will be generated for the overall 
period.
The number & percentage of subjects with post-baseline values listed below will be summarized 
by treatment arm

at least one post-baseline value <=5 mmHg, >5 to <=21 mmHg, >21 to <=30 mmHg, 
and >30mmHg by eye side (right, left, worst)

the Increase from baseline IOP >=5mmHg to <10 mmHg & >= 10mmHg by eye side 
(right, left, best)

the Decrease from baseline IOP >=5mmHg to <10 mmHg & >= 10mmHg by eye side 
(right, left, worst)
A listing of subjects will also be provided for this assessment.
Intraocular pressure will also be summarized in shift table (baseline and post baseline value at 
each time point) for each eye side considering the following categories: ≤5, >5 to ≤21, >21 to 
≤30 and > 30 mmHg for each of the treatment arms.
Slit Lamp 
For each considered evaluation type (Lids, Cornea, Conjunctiva, Iris, Anterior chamber, 
Aqueous flare, Aqueous inflammatory cells, Lens) and eye side, the number & percentage of 
subjects with and without abnormality (normal, insignificant, clinically significant) will be 
provided by timepoint and treatment arm. Further, shift tables will be generated for each eye, 
evaluation type, and treatment arm by time point separately. In addition, for each slit lamp 
evaluation, shift tables will be generated to present the worst post-baseline changes compared 
to baseline by treatment arm and eye side. A listing of subjects with any abnormality will be 
provided. Subjects with abnormalities recorded in free text of “Abnormalities” section of the 
“Ophthalmic Examinations - Slit Lamp Exam” CRF for the following eye parts - lids/lashes, 
cornea, conjunctiva, iris & anterior chamber will be coded using MedDRA (version 26.0 ) and 
these coded ocular terms will be summarized using frequency counts and percentages by 
timepoints.  Further, subjects with abnormalities recorded in free text of “Abnormalities” 
section of the “Ophthalmic Examinations - Slit Lamp Exam” CRF abnormalities for the 
following eye parts – aqueous flare, aqueous inflammatory cells, lens will be reported as 
recorded in CRF by frequency and percentages. A listing for the MedDRA coded ocular terms 
will also be presented. 


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Lens Opacification
The Lens opacification will be measured by the LOCSIII with categories as mentioned in the 
CRF. These assessments will be summarized using shift tables – the changes in LOCSIII grade 
will be presented for each eye, evaluation type (Nuclear Color, Nuclear Opalescence, Cortical,
Posterior Subcapsular) and treatment arm by time point. Additionally, the worst change in grade
compared to baseline for each eye, evaluation type, and treatment arm will also be presented 
using shift tables. Swimmer plots will be generated to show the categories of LOCSIII at 
baseline versus scheduled visits for each of the evaluation types by treatment arm and eye side. 
The treatment duration will also be displayed on the plot. A listing of subjects will be provided.
Fundus Oculi
For each considered evaluation type (Peripheral Retina, Macula, Optic Nerve, & Vitreous 
Hemorrhage) and eye side, the number & percentage of subjects with and without abnormality
will be provided by timepoint, eye side and treatment arm. In addition, shift table will be 
generated to present the worst post-baseline changes compared to baseline by eye side and 
treatment arm. A listing of subjects with any abnormality will be provided. Subjects with 
abnormalities recorded in free text of “Other Findings (Abnormalities)” section of the “Dilated 
Fundus Examination” CRF will be coded using MedDRA (version 26.0) and these coded ocular 
terms will be summarized by timepoints using frequency counts and percentages. A listing for 
the MedDRA coded ocular terms will also be presented. 
Color Fundus Photography
The Color Fundus Photography Assessment will be conducted by a central vendor though 
photographs. For each considered evaluation type and eye side, the number & percentage of 
subjects with and without abnormality will be provided by timepoint and treatment arm. A 
listing of subjects will be provided; additionally, listings for the findings, general comments 
and confidence score comments will be presented.
2.6.3
Adverse Events (AEs)
Adverse Event summaries will include all AEs occurring during on treatment period (see 
Section 2.1.1). 
In AE summaries, the primary system organ class will be presented alphabetically, and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the Deferasirox FCT arm.
The following adverse event summaries will be produced by treatment arm. A subject with 
multiple occurrences of an AE will be counted only once in the respective AE category. 

Adverse events, regardless of study treatment relationship by primary system organ 
class, preferred term, and severity (mild, moderate & severe)

Adverse events with suspected study treatment relationship by primary system organ 
class, preferred term, and severity


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
Serious adverse events, regardless of study treatment relationship, by primary system 
organ class, preferred term, and severity

Serious adverse events, with suspected study treatment relationship, by primary system 
organ class, preferred term, and severity

Adverse events leading to study treatment discontinuation, regardless of study drug 
relationship, by primary system organ class, preferred term, and severity

Adverse events requiring dose adjustment or study treatment interruption, regardless of 
study treatment relationship, by primary system organ class, preferred term, and severity

Adverse events requiring additional therapy, regardless of study treatment relationship, 
by primary system organ class, preferred term, and severity

Deaths (all and on-treatment) by primary system organ class and preferred term
To assess the secondary safety objective on evaluation of safety and tolerability of deferasirox 
FCT in subjects who interrupt due to SF ≤ 100 μg/L and re-initiate therapy when ≥ 300 μg/, the 
number (%) of subjects who met the criteria of interruption due to SF ≤ 100 μg/L and re-
initiation of therapy when ≥ 300 μg and interruption due to SF ≤ 100 μg/L will be summarized
respectively. 
The summaries from above (barring the last two) will be repeated for subjects who interrupted 
deferasirox FCT at least once due to SF ≤ 100 μg/L and re-initiated ≥ 300 μg/L will be tabulated.
If less than 10 subjects meet the above criteria, only listings will be generated. 
AEs will be summarized by presenting the number and percentage of subjects having at least
one AE, and having at least one AE by system organ class and preferred, severity and relation 
to study treatment by arm. A subject with multiple occurrences of an AE will be counted only 
once in the worst AE category (if it occurs in multiple categories).
An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation,
requiring dose adjustment or/and interruption) will be presented by severity and treatment arm.
Additionally, for those with dose interruptions (FCT re-initiation), the overall summary for the 
AEs will generated as described above.
All AEs will be listed. Any information collected (e.g. regardless to study drug, action taken
etc.) will be listed as well as the duration of the AE. 
The listings of all deaths, serious adverse events, adverse events leading to study drug 
discontinuation, and adverse events requiring dose adjustment or interruption will also be 
provided.
Summaries of COVID related adverse events as defined in the eCRS will be provided by 
treatment arm. A listing of COVID related AEs and deaths will also be generated.
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.


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2.6.4
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term (primary reason of death). 
All deaths will be listed, pre-treatment (if any) and post treatment deaths will be flagged. 
2.6.5
Adverse Events of Special Interest (AESI)
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound ICL670. These groupings are defined in the eCRS using 
MedDRA terms, SMQs, HGLTs (high level group terms), HLT and PTs. Customized SMQs 
(NMQ) may also be used. A NMQ is a customized group of search terms which defines a 
medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad. The latest version of the eCRS available at the time of the analysis will be 
used.
For each specified AESI, number and percentage of subjects with at least one event of the AESI 
occurring during on treatment period will be summarized.
Summaries of these AESIs will be provided for each of the two treatment arms by grouping and 
preferred term –

AESIs, regardless of study treatment relationship 

AESIs, with suspected study treatment relationship 

Serious AESIs regardless of study treatment relationship

Serious AESIs with suspected study treatment relationship

AESIs leading to study treatment discontinuation

AESIs requiring dose adjustment or study treatment interruption

AESIs requiring additional therapy

AESIs Outcomes – Recovered or Recovering

Deaths (all and on-treatment) 
A listing of all grouping levels down to the MedDRA preferred terms used to define each 
AESI will be generated. 
2.6.6
Disclosure Related Outputs 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables will be 
produced for the Safety Set at the time of the final CSR:

Non-serious adverse events with an incidence greater than 5%

Serious adverse events (SAE) and SAE suspected to be related to study treatment will 
be provided by system organ class and preferred term. The number of deaths resulting 
from SAEs suspected to be related to study treatment and SAEs irrespective will also 
be provided.
If for a same subject, several consecutive AEs (irrespective of study treatment causality,
seriousness and severity) occurred with the same SOC and PT:


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
A single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

More than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
2.6.7
Laboratory Data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than 30 days after the last study treatment administration date (see Section 2.1.1).
The following summaries will be produced for hematology, urinary, and biochemistry 
laboratory data (by laboratory parameter and treatment):

Descriptive Statistics for lab results and change by from baseline time point and treatment 
arm 

Shift tables using notable/extended ranges to compare baseline to the worst on-treatment
value for key lab parameters (see Table 2-1)

Shift tables using the low/normal/high/(low and high) classification to compare baseline to 
the worst on-treatment value.

Trends of key lab parameter values over time (baseline and selected on-treatment 
timepoints) will be displayed via boxplots based on time windows and corresponding 
tables displaying the statistics used for the box plots by the selected time points. 
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with classification relative to the laboratory normal range. 

Listing of all lab abnormalities based on notable/extended ranges 
Table 2-1 Definition of notable/extended ranges for key safety laboratory parameters
Parameter
Criteria
Absolute neutrophils
< 1.5×109/L (extended range < 0.5×109/L)
Platelets
< 100×109/L (extended range < 50×109/L)
Hemoglobin
< 100 g/L
ALT and AST
> 5× ULN and > 2× baseline (extended range > 10× ULN and > 2× 
baseline)
Total bilirubin
> 2 x ULN
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 least 7 days apart)
Urinary protein/creatinine ratio*
≥ 1.0 mg/mg at 2 consecutive measurements at least 7 days apart


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* If the unit of the parameter (Urinary protein/creatinine ratio) is in mg/mmol then will have to 
use a conversion factor as 0.00885 to convert into mg/mg unit for further derivation.  
For all analyses, creatinine clearance will be re-derived using the Cockcroft-Gault equation
described in Section 5.2.1. 
Liver Function Parameters
Liver function parameters of interest are total bilirubin (TBL), Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%) of subjects 
with worst post-baseline values as per Novartis Liver Toxicity guidelines will be summarized.
The following summaries will be produced:

ALT > 3xULN 

ALT > 5xULN

ALT > 8xULN

ALT > 10xULN

ALT > 20xULN

AST > 3xULN 

AST > 5xULN

AST > 8xULN

AST > 10xULN

AST > 20xULN

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP >= 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN
A figure displaying time course of hepatic function tests (ALT, AST, TBL, ALP) in subjects 
with Hy’s law (ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN) will be displayed 
in the Safety Set.


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2.6.8
Vital Signs and Weight 
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings.
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-2
below and the windowing for vital signs are in Table 5-3. 
Table 2-2 Definition of notable ranges for vital signs and weight
Parameter
Criteria for notable ranges
Systolic blood pressure
≥ 180 mmHg / ≤ 90 mmHg with increase / decrease from baseline ≥ 20 mmHg
Diastolic blood pressure
≥ 105 mmHg / ≤ 50 mmHg with increase / decrease from baseline ≥ 15 mmHg
Pulse rate
≥ 120 bpm / ≤ 50 bpm with increase / decrease from baseline ≥15 bpm
Weight
≥ 10% increase or decrease
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented by treatment arm.    
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged. 
2.6.9
Other Safety Data
The number and percentage of subjects with clinically significant abnormalities in ECG test 
and auditory evaluation will be presented by treatment arm. A listing of all ECG and auditory 
assessments will be produced by treatment arm and the assessments collected during the post-
treatment period will be flagged. 
Results from pregnancy tests will be listed and positive results will be flagged.
3
Sample Size Calculation
The primary objective of the study is to estimate response rates and therefore the sample size is 
not based on power calculations. Sample size calculations were performed for the deferasirox 
FCT and phlebotomy arms to estimate the response rate with reasonable accuracy (half-width 
of 95% confidence interval). 
Based on the Exjade study ICL670A2202, the subject dropout rate at month 6 (core study) is 
24% and 12% at month 12 (optional extension phase). Assuming decreasing dropout rate over 
time and expected better subject compliance with deferasirox FCT formulation, a sample size 
of 100 subjects in the FCT arm is expected to have at least 60 subjects followed for 24 months 
to fulfil the FDA post-marketing requirement with regard to the ocular toxicity assessment in 
subjects receiving deferasirox. 
With a sample size of 100 on deferasirox FCT and 50 subjects on phlebotomy, the projected 
half-widths of the 2-sided 95% confidence interval assuming various response rates are 
displayed in Table 3-1. The 95% confidence interval half-width extends at most to 0.096 and 
0.136 in the deferasirox FCT and phlebotomy arms, respectively.


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Table 3-1 Half-width of 95% CI of response rates in deferasirox FCT and phlebotomy arms 
Response rate (RR)
Half-width of the 95% CI for 
deferasirox FCT 
N=100
Half-width of the 95% CI for 
phlebotomy 
N=50
0.60
0.096
0.136
0.65
0.093
0.132
0.70
0.090
0.127
0.75
0.085
0.120
0.80
0.078
0.111
0.85
0.070
0.099
0.90
0.059
0.083
4
Change to protocol specified analyses
Additional analysis related to COVID-19 related AEs and COVID-19 specific protocol 
deviations (Section 2.2.1 and Section 2.6.3)  added. Due to COVID-19, the scheduled 
assessments had delays and consequently the subjects’ assessments were unscheduled. 
Therefore, the Ocular windowing for the scheduled assessments was updated (see details in 
Section 5.3.2).
5
Appendix
5.1
Imputation Rules
5.1.1
Study Treatment
The following rule should be used for the imputation of date of last administration:
Scenario 1: If the date of last administration is completely missing and there is no EOT eCRF 
page, the subject is considered as on-going. The subject should be treated as on-going, and the 
cut-off date should be used as the last dosing date.
Scenario 2: If the date of last administration is completely or partially missing and the EOT 
eCRF page is available (prior to any death date or withdrawal of consent date, if available): 
Case 1: The date of last administration is completely missing, and the EOT visit date is complete, 
then this latter date should be used.
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:
      Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date: 
      Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy = the year of EOT date and mm < the month of EOT visit:
      Use last day of the Month (mm).


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After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record
      Use the start date of that record.
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If the date of first administration is missing, 
then the date of last administration should not be imputed.
There will be no attempt to impute any other date from eCRF ZQ page. 
5.1.2
AE, Concomitant medications and safety assessment date Imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than study treatment 
start date then set start date = 01JanYYYY >
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than study treatment 
start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start date then 
01MONYYYY  

If available month and year < month year of study treatment start date then 
15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(*=last treatment date plus <30> days not > (death date, cut-off date, withdrawal of 
consent date))
day, month, 
and year
Completely missing end dates (incl. ongoing events) will be imputed by the end date of 
the on-treatment period* 
day, month
If partial end date contains year only, set end date = earliest of 31DecYYYY or end date 
of the on-treatment period * 
day
If partial end date contains month and year, set end date = earliest of last day of the 
month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ rather than the end 
date provided. 


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5.1.3
Prior and Concomitant Medication Date Imputation
The imputation of the start date of concomitant medication will follow the same conventions as 
for AE start date. 
5.1.4
Incomplete Date of Diagnosis of Hemochromatosis History
Incomplete dates for date of diagnosis will be imputed with the earliest possible date, provided 
that at least the year of diagnosis is known, and that imputed diagnosis date occurred before 
screening visit 1.
5.2
Laboratory Parameters Derivations
5.2.1
Re-derived Creatinine Clearance
The re-derived creatinine clearance will be calculated using the Cockcroft-Gault equation.
In the formulae below, CrCl denotes Creatinine Clearance in mL/min, SCr denotes Serum 
Creatinine in µmol/L; age in years is calculated from date of birth and date of the relevant blood 
sample. Weight and height are the last available measurements at the time of the relevant blood 
sample.
Cockcroft-Gault formula (≥18 years of age), 
CrCl (mL/min)=
Male subjects: (140-age (years)) ×weight (kg)/(815×0.001×SCr (µmol/L))
Female subjects: (140-age (years)) ×weight (kg)×0.85/(815×0.001×SCr(µmol/L))
5.2.2
Multiple Assessments Within Post-Baseline Visits
All scheduled/unscheduled assessments should be assigned to time windows. In case of multiple 
values per window, the one closest to the planned visit date should be used. If 2 values are 
equidistant to the planned visit date, the selection should be made by selecting the one assessed 
by central (if any) and otherwise - for multiple central assessments equidistant to the planned 
visit - the last value. When multiple values are reported on the same day then the average value 
is used in analyses. 
For worst post-baseline assessment, all on-treatment values are considered regardless of time 
windows. All unscheduled and repeat measurements will be included in listings.
5.3
Time-Windows
5.3.1
Safety Laboratory Assessments
Safety laboratory data (biochemistry, hematology, and urinary parameters as well as serum 
creatinine, creatinine clearance and proteinuria) will be collected at screening visits, at each 
regularly subject visit and at end of treatment visit. 


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If two or more assessments are performed within a time window, then the assessment closest to 
the planned visit is used in analyses by time window. When two values are equidistant from the 
planned assessment, the later one is used in analyses. When multiple values are reported on the 
same day then the average value is used in analyses. For parameters with categorical results, 
the one from central laboratory is used in analyses.
Table 5-3 shows the defined time windows.
Table 5-3 Time windows for safety laboratory 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* 8
Study Days 2 – 11 (excluded 
baseline assessment)
Week 4 
Study Day* 22
Study Days 19 – 25
Every 4 weeks thereafter 
Week y=4+(4*k) 
(with k = 1, 2, 3, 4, 5, 6, 7, 8, 9, 
10, 11,…,25)
Study Day (4+4*k-1)*7+1 
Study Days 
(5+4*k-1)*7+1-14 to 
(5+4*k-1)*7+1+13
End of treatment
NA
Data collected at EOT visit are 
included if obtained within the next 
30 days of last non-0 dose for DFX 
intake / non 0 volume removed for 
Phlebotomy
*Study Day 1 = first day of study treatment
5.3.2
Ocular Assessments
Ocular data will be collected at screening visit, at week 24, 52, 76, 104 (EOT) visits. If two or 
more assessments performed within a time window, then the assessment closest to the planned 
visit is used in analyses by time window. When two values are equidistant from the planned 
assessment, the later one is used in analyses. The windowing defined is applicable for both on-
treatment & post-treatment time periods. For the summaries by time point, we will be presenting 
the time points as defined below (Table 5-3). 
For worst post-baseline assessment, all on-treatment values and post treatment values are 
considered regardless of time windows.
Table 5-4 shows the defined time windows.
Table 5-4 Time windows for Ocular data
Time point (Weeks)
Study Day
Lower Limit (day)
Upper Limit (day)
Baseline (Screening)
1*
-30
1
Week 24
162
2
259
Week 52
358
260
441
Week 76
526
442
623
Week 104
722
624
819


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Confidential
Page 35 of 36
SAP Amendment 1
Study No. CICL670F2203
End of Treatment - Data collected at the EOT visit if conducted within 30 days of EOT date on disposition 
(DS) page in CRF.
For the post-baseline assessments among discontinued subjects, if no data were collected at the EOT visit the 
last available post-baseline on-treatment data will be used for EOT.
*Study Day 1 = first day of study treatment


Novartis
Confidential
Page 36 of 36
SAP Amendment 1
Study No. CICL670F2203
6
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