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Clinical Trial Results:
A randomized, double-blind, placebo-controlled, phase II study to evaluate efficacy and safety of deferasirox in nontransfusion-dependent thalassemia patients with iron overload (THALASSA) A one-year open-label extension to a randomized, double-blind, placebo-controlled, phase II study to evaluate efficacy and safety of deferasirox in non-transfusion-dependent thalassemia patients with iron overload (THALASSA)

Summary
EudraCT number	2007-007000-15
Trial protocol	GB IT GR
Global end of trial date	13 Jun 2012

Results information
Results version number	v1(current)
This version publication date	29 Jul 2016
First version publication date	29 Jul 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CICL670A2209/E1

ISRCTN number

US NCT number

NCT00873041

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001103-PIP01-10

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

13 Jun 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Jun 2012

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of two regimens of deferasirox administration (starting doses of 5 and 10 mg/kg/day) in patients with NTDT based on change in LIC from baseline after one year of treatment compared to placebo-treated patients and A one-year open-label extension to a randomized, double-blind, placebo-controlled, phase II study to evaluate efficacy and safety of deferasirox in non-transfusion-dependent thalassemia patients with iron overload (THALASSA)

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Rescue medication was not allowed during the course of the study. The investigator provided follow-up medical care for all subjects who were prematurely withdrawn from the study, or referred them for appropriate ongoing care.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Nov 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 4

Country: Number of subjects enrolled

Turkey: 16

Country: Number of subjects enrolled

Malaysia: 10

Country: Number of subjects enrolled

Thailand: 55

Country: Number of subjects enrolled

Lebanon: 29

Country: Number of subjects enrolled

Taiwan: 1

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

Greece: 12

Country: Number of subjects enrolled

Italy: 31

Worldwide total number of subjects

166

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

144

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 24 centres in 9 countries.

Screening details

A total of 166 subjects were randomized and treated in the core period. Out of the 148 subjects who completed the core study, 133 subjects were enrolled to extension period.

Period 1 title

Core period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Blinding implementation details

Randomization data were kept strictly confidential and the identity of treatments were concealed by the use of identical study drugs. Unblinding was allowed from randomization to database lock, except in case of subject emergencies and at the conclusion of the study.

Are arms mutually exclusive

Yes

Deferasirox 5 mg/kg/day (Core)

Arm description

Subjects were administered with deferasirox at a starting dose of 5 mg/kg daily through oral route based on daily iron removal. The dose was up-titrated to 10 mg/kg if LIC assessment indicated insufficient iron chelation (LIC > 7 mg Fe/g dw and LIC reduction < 15% compared to baseline) at Week 24.

Arm type

Experimental

Investigational medicinal product name

Deferasirox

Investigational medicinal product code

ICL670

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Deferasirox 5 mg/kg daily was administered orally as starting dose.

Deferasirox 10 mg/kg/day (Core)

Arm description

Subjects were administered with deferasirox at a starting dose of 10 mg/kg daily through oral route based on daily iron removal. The dose was up-titrated to 20 mg/kg if LIC assessment indicated insufficient iron chelation (LIC > 7 mg Fe/g dw and LIC reduction < 15% compared to baseline) at Week 24.

Arm type

Experimental

Investigational medicinal product name

Deferasirox

Investigational medicinal product code

ICL670

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Deferasirox 10 mg/kg daily was administered orally as starting dose.

Placebo (Core)

Arm description

Placebo matched to deferasirox was administered in subjects daily through oral route.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matched to deferasirox was daily administered in subjects orally.

Number of subjects in period 1	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)
Started	55	55	56
Completed	48	49	51
Not completed	7	6	5
Consent withdrawn by subject	1	2	2
Adverse event, non-fatal	2	3	1
Abnormal laboratory value	-	-	1
Lost to follow-up	3	1	-
Protocol deviation	1	-	1

Period 2 title

Extension period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Deferasirox any dose (Extension)

Arm description

Subjects were administered with deferasirox at a starting dose of 5 mg/kg and 10 mg/kg daily through oral route based on daily iron removal. The dose was up-titrated to 10 mg/kg and 20 mg/kg if LIC assessment indicated insufficient iron chelation (LIC > 7 mg Fe/g dw and LIC reduction < 15% compared to baseline) at Week 24.

Arm type

Experimental

Investigational medicinal product name

Deferasirox

Investigational medicinal product code

ICL670

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Deferasirox 5 mg/kg and 10 mg/kg daily was administered orally as starting dose. The dose was up-titrated to 10 mg/kg and 20 mg/kg if LIC assessment indicated insufficient iron chelation (LIC > 7 mg Fe/g dw and LIC reduction < 15% compared to baseline) at Week 24.

Placebo/Deferasirox any dose (Extension)

Arm description

Open label deferasirox was administered in subjects daily through oral route of patients formerly on placebo

Arm type

Experimental

Investigational medicinal product name

Deferasirox

Investigational medicinal product code

ICL670

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Deferasirox 5 mg/kg daily was administered orally as starting dose.

Number of subjects in period 2 ^[1]	Deferasirox any dose (Extension)	Placebo/Deferasirox any dose (Extension)
Started	85	48
Completed	84	46
Not completed	1	2
Adverse event, non-fatal	1	1
Administrative reasons	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: The number of subjects reported in the baseline period are different from the worldwide number enrolled in the trial, as of 148 subjects who completed the preceding period, only 133 subjects opted to enroll in extension study.

Baseline characteristics

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Reporting group title

Deferasirox 5 mg/kg/day (Core)

Reporting group description

Reporting group title

Deferasirox 10 mg/kg/day (Core)

Reporting group description

Reporting group title

Placebo (Core)

Reporting group description

Placebo matched to deferasirox was administered in subjects daily through oral route.

Reporting group values	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)	Total
Number of subjects	55	55	56	166
Age categorical
Units: Subjects
2 years to < 18 years	6	7	8	21
18 years to <50 years	44	45	42	131
50 years to <65 years	5	2	6	13
>=65 years	0	1	0	1
Age continuous
Units: years
arithmetic mean (standard deviation)	33.1 ( 12.3 )	31.7 ( 11.68 )	31.4 ( 12.23 )	-
Gender categorical
Units: Subjects
Female	26	26	25	77
Male	29	29	31	89

End points

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Reporting group title

Deferasirox 5 mg/kg/day (Core)

Reporting group description

Reporting group title

Deferasirox 10 mg/kg/day (Core)

Reporting group description

Reporting group title

Placebo (Core)

Reporting group description

Placebo matched to deferasirox was administered in subjects daily through oral route.

Reporting group title

Deferasirox any dose (Extension)

Reporting group description

Reporting group title

Placebo/Deferasirox any dose (Extension)

Reporting group description

Open label deferasirox was administered in subjects daily through oral route of patients formerly on placebo

Subject analysis set title

All randomized subjects (Core study)

Subject analysis set type

Full analysis

Subject analysis set description

Subjects were administered with deferasirox at a starting dose of 5 mg/kg, 10 mg/kg and matching placebo daily through oral route based on daily iron removal. The dose was up-titrated to 10 mg/kg and 20 mg/kg if LIC assessment indicated insufficient iron chelation (LIC > 7 mg Fe/g dw and LIC reduction < 15% compared to baseline) at Week 24.

Subject analysis set title

All deferasirox treated subjects (Extension study)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

All randomized subjects (Extension study)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

All placebo treated subjects (Extension study)

Subject analysis set type

Full analysis

Subject analysis set description

Subjects were administered with deferasirox matching placebo daily through oral route.

Primary: Change in Liver Iron Concentration (LIC) from baseline to week 52

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End point title

Change in Liver Iron Concentration (LIC) from baseline to week 52

End point description

Liver iron concentration (LIC), a predictor of iron burden, was measured using relaxation rate magnetic resonance imaging (R2-MRI) technique. Relaxation rate was determined as R2 = 1/relaxation time (T2). The baseline value of LIC of subjects was categorized as < 5, 5-7, ≥ 7 to < 15, and ≥ 15 milligram of iron/tissue dry weight (mgFe/g dw). A negative change from baseline favoured study treatment in reducing LIC. The analysis was performed in the Full Analysis Set (FAS) population, defined as all randomized subjects. The last available post-baseline LIC was carried forward if no LIC value was available at Week 52. Here, "Number of subjects analysed" signifies the subjects assessed for LIC during the core period for each arm, respectively. Only subjects with both baseline and at least one post baseline value were included for the analysis.

End point type

Primary

End point timeframe

Baseline to Week 52 (Month 12: End of core study period)

End point values	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)
Number of subjects analysed	51	54	54
Units: mg Fe/g dw
least squares mean (standard error)	-1.95 ( 0.5 )	-3.8 ( 0.484 )	0.38 ( 0.486 )

Change in LIC deferasirox 5 mg/kg v/s 10 mg/kg

Statistical analysis description

Estimates were obtained from an Analysis of Covariance (ANCOVA) model for change in LIC with treatment as factor and baseline LIC as covariate. Two-sided p-value testing the hypothesis that the change in LIC is identical in the two deferasirox groups.

Comparison groups

Deferasirox 10 mg/kg/day (Core) v Deferasirox 5 mg/kg/day (Core)

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.009

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-1.85

Confidence interval

level

95%

sides

2-sided

lower limit

-3.22

upper limit

-0.48

Variability estimate

Standard error of the mean

Dispersion value

0.695

Difference of deferasirox 5 mg/kg v/s Placebo

Comparison groups

Deferasirox 5 mg/kg/day (Core) v Placebo (Core)

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-2.33

Confidence interval

level

95%

sides

2-sided

lower limit

-3.89

upper limit

-0.76

Variability estimate

Standard error of the mean

Dispersion value

0.7

Difference of deferasirox 10 mg/kg v/s Placebo

Comparison groups

Placebo (Core) v Deferasirox 10 mg/kg/day (Core)

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-4.18

Confidence interval

level

95%

sides

2-sided

lower limit

-5.71

upper limit

-2.64

Variability estimate

Standard error of the mean

Dispersion value

0.687

Primary: LIC responses by the end of the extension phase

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End point title

LIC responses by the end of the extension phase ^[1]

End point description

LIC, a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC of subjects was categorized as < 5, 5-7, ≥ 7 to < 15, and ≥ 15 mg Fe/g dw. The subjects with LIC < 5 mg Fe/g dw change from baseline to end of the extension period were reported. Subjects with post-baseline LIC satisfying criteria were considered as responder. The analysis was performed in the FAS population.

End point type

Primary

End point timeframe

Baseline (Core study) to End of Extension study (24 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive summary statistics was planned for this outcome measure.

End point values	All placebo treated subjects (Extension study)	All deferasirox treated subjects (Extension study)
Number of subjects analysed	56	110
Units: Percentage of subjects
number (confidence interval 95%)	37.5 (26 to 56)	39.1 (30.5 to 48.4)

No statistical analyses for this end point

Secondary: Change in Liver Iron Concentration (LIC) from baseline to Week 24

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End point title

Change in Liver Iron Concentration (LIC) from baseline to Week 24

End point description

LIC, a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC of subjects was categorized as < 5, 5-7, ≥ 7 to < 15, and ≥ 15 mg Fe/g dw. A negative change from baseline favoured study treatment in reducing LIC. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies the subjects assessed for LIC during the core and extension period for each arm, respectively. The last available post-baseline LIC was carried forward if no LIC value was available at Week 24 and Month 24 for core and extension period, respectively.

End point type

Secondary

End point timeframe

Baseline (Core study), Week 24 (Core study)

End point values	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)
Number of subjects analysed	49	48	51
Units: mg Fe/g dw
least squares mean (standard error)	-0.87 ( 0.448 )	-0.9 ( 0.45 )	-0.24 ( 0.439 )

No statistical analyses for this end point

Secondary: Change in serum ferritin from baseline to second and fourth quarter

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End point title

Change in serum ferritin from baseline to second and fourth quarter

End point description

Change from baseline: second and fourth quarter average serum ferritin - baseline average serum ferritin. Serum ferritin changes were defined as the difference between post-baseline average - baseline average and ratio of post-baseline average/baseline average. Serum ferritin < 100 microgram (mcg)/mL was considered notable. Second quarter average serum ferritin was defined as the average of all serum ferritin values obtained within days 106 to 195. Fourth quarter average serum ferritin was defined as the average of all serum ferritin values obtained within days 286 to end of study. Negative change from baseline indicates reduced iron burden. The analysis was performed in the FAS population. The last available average of serum ferritin per quarter was carried forward if no serum ferritin was available during the fourth quarter. Here, "Number of subjects analysed" signifies the subjects assessed for serum ferritin during the core period for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline, (Day 106 to Day 195), (Day 286 up to End of study [Day 365])

End point values	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)
Number of subjects analysed	52	54	56
Units: Microgram/litre
arithmetic mean (standard deviation)
Second quarter (n= 52, 54, 56)	8.2 ( 244.443 )	-17.75 ( 368.812 )	106.45 ( 330.217 )
Fourth quarter (n= 51, 50, 53)	-130.47 ( 260.555 )	-249.16 ( 389.356 )	128.63 ( 249.689 )

No statistical analyses for this end point

Secondary: Change in Liver Iron Concentration (LIC) from baseline to Week 24 and to Week 52 in subjects with escalated dose after Week 24

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End point title

Change in Liver Iron Concentration (LIC) from baseline to Week 24 and to Week 52 in subjects with escalated dose after Week 24

End point description

LIC, a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. Dose of deferasirox was doubled if at Week 24 LIC assessment indicated insufficient iron chelation (LIC >7 mg Fe/g dw and LIC reduction <15% compared to baseline). A negative change from baseline favoured study treatment in reducing LIC. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies the subjects with dose increases after week 24, with both baseline and at least one post-baseline value. The last available post-baseline LIC was carried forward if no LIC value was available at Week 24 and Week 52.

End point type

Secondary

End point timeframe

Baseline, Week 24, Week 52

End point values	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)
Number of subjects analysed	26	25	30
Units: mg Fe/g dw
arithmetic mean (standard deviation)
Change from baseline at Week 24 (n=26,24,30)	0.56 ( 2.992 )	0.69 ( 3.131 )	0.94 ( 2.693 )
Change from baseline at Week 52 (n= 26,25,30)	-1.82 ( 3.101 )	-4.02 ( 4.849 )	0.62 ( 4.128 )

No statistical analyses for this end point

Secondary: Correlation between Serum Ferritin and LIC (Liver Iron Concentration)

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End point title

Correlation between Serum Ferritin and LIC (Liver Iron Concentration)

End point description

The correlation between absolute change in serum ferritin and absolute change in LIC was determined using a scatter plot with a regression line for serum ferritin versus LIC from baseline at Week 52. A value of 1.0 indicates a perfect correlation. The analysis was performed in the FAS population of core study. Subjects with LIC and serum ferritin values at the specified time points were included in analysis

End point type

Secondary

End point timeframe

Baseline (Core study), Week 52 (End of core study), Month 24 (End of extension study)

End point values	All randomized subjects (Core study)	All randomized subjects (Extension study)
Number of subjects analysed	165	129
Units: Correlation coefficient
number (not applicable)	0.639	0.735

No statistical analyses for this end point

Secondary: Change in haemoglobin absolute levels from baseline to Week 52 and Month 24

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End point title

Change in haemoglobin absolute levels from baseline to Week 52 and Month 24

End point description

Absolute change from baseline was defined as weekly average – baseline average of haemoglobin absolute levels. A negative change from baseline indicated improvement. The analysis was performed in the FAS population of core study. Here, "Number of subjects analysed" signifies the subjects with values both at baseline and at Week 52 for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline (Core study), Week 52 (End of core study), Month 24 (End of extension study)

End point values	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)
Number of subjects analysed	55 ^[2]	55 ^[3]	56 ^[4]
Units: Gram/litre
arithmetic mean (standard deviation)
12 months	-1.8 ( 5.5 )	-0.6 ( 6.1 )	-3 ( 7.7 )
24 months	-3.9 ( 5.55 )	-1.2 ( 6.41 )	-3.1 ( 9.48 )

Notes
[2] - month 12 n=45 month 24 = 31
[3] - month 12 n=47 month 24 n=28
[4] - month 12 n=45 month 24 n=29

No statistical analyses for this end point

Secondary: Change in transferrin saturation levels from baseline to Week 52 and Month 24

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End point title

Change in transferrin saturation levels from baseline to Week 52 and Month 24

End point description

Absolute change from baseline was defined as weekly average – baseline average for transferrin saturation levels. A negative change from baseline indicated improvement. The analysis was performed in the FAS population of core study. Here, "Number of subjects analysed" signifies the subjects with values both at baseline and at Week 52 and month 24 for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline (Core study), Week 52 (End of core study), Month 24 (End of extension study)

End point values	Deferasirox 5 mg/kg/day (Core)	Deferasirox 10 mg/kg/day (Core)	Placebo (Core)
Number of subjects analysed	55 ^[5]	55 ^[6]	56 ^[7]
Units: Percent saturation
arithmetic mean (standard deviation)
month 12	-3.76 ( 11.762 )	-3.13 ( 20.973 )	2.42 ( 9.031 )
month 24	-7.93 ( 22.037 )	-2.26 ( 26.394 )	1.35 ( 13.013 )

Notes
[5] - month12 n=38 month 24 n=32
[6] - month12 n=31 month 24 n=34
[7] - month12 n=36 month 24 n=33

No statistical analyses for this end point

Secondary: Absolute change in liver iron concentration (LIC) in placebo treated subjects from baseline to Week 52

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End point title

Absolute change in liver iron concentration (LIC) in placebo treated subjects from baseline to Week 52

End point description

Change in LIC was measured using relaxation R2-MRI technique at Week 24, Week 52 and last available LIC after stopping the treatment. The change in liver iron concentration for placebo treated subjects was used to assess the iron accumulation rate in pooled placebo subjects. The analysis was performed in the FAS population. The last available post-baseline LIC was carried forward if no LIC value was available at Week 52. Here, "Number of subjects analysed" signifies the subjects assessed for LIC during the core period for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All randomized subjects (Core study)
Number of subjects analysed	54
Units: mg Fe/g dw
arithmetic mean (standard deviation)	0.26 ( 3.501 )

No statistical analyses for this end point

Secondary: Absolute change in serum ferritin from baseline to eighth quarter

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End point title

Absolute change in serum ferritin from baseline to eighth quarter

End point description

Change from baseline: second and fourth quarter average serum ferritin - baseline average serum ferritin. Serum ferritin changes were defined as the difference between post-baseline eighth quarterly average – baseline average and ratio of post-baseline average/baseline average. Serum ferritin < 100 mcg/mL was considered notable. A negative change from baseline indicated improvement. The analysis was performed in the FAS population of extension study. Subjects with both baseline and at least one post baseline value were included for this analysis. Here, "Number of subjects analysed" signifies the subjects assessed for serum ferritin during the extension period for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline (Core study), Eighth Quarter (last 3 months of extension study)

End point values	Deferasirox any dose (Extension)	Placebo/Deferasirox any dose (Extension)
Number of subjects analysed	84	46
Units: Milligram(s)/litre
arithmetic mean (standard deviation)	-565.9 ( 504.25 )	-504.3 ( 770.6 )

No statistical analyses for this end point

Secondary: Absolute change in LIC for subjects who stopped deferasirox treatment

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End point title

Absolute change in LIC for subjects who stopped deferasirox treatment

End point description

Iron accumulation rate was evaluated for change in LIC from therapy stop for 6 month and for last available LIC measurement. The absolute change in LIC for subjects who stopped treatment was used to assess the iron accumulation rate. The analysis was performed in the SAF population of extension study. Here, "Number of subjects analysed" signifies the subjects assessed for LIC during the extension period for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline (Core study), Month 12 (End of core study), Month 24 (End of extension study)

End point values	All deferasirox treated subjects (Extension study)
Number of subjects analysed	24 ^[8]
Units: mg Fe/g dw
arithmetic mean (standard deviation)	0.73 ( 0.621 )

Notes
[8] - subjects who stopped deferasirox treatment

No statistical analyses for this end point

Secondary: Change in Liver Iron Concentration (LIC) from baseline Month 24

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End point title

Change in Liver Iron Concentration (LIC) from baseline Month 24

End point description

LIC, a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC of subjects was categorized as < 5, 5-7, ≥ 7 to < 15, and ≥ 15 mg Fe/g dw. A negative change from baseline favoured study treatment in reducing LIC. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies the subjects assessed for LIC during the core and extension period for each arm, respectively. The last available post-baseline LIC was carried forward if no LIC value was available at Week 24 and Month 24 for core and extension period, respectively.

End point type

Secondary

End point timeframe

baseline and month 24

End point values	Deferasirox any dose (Extension)	Placebo/Deferasirox any dose (Extension)
Number of subjects analysed	84	46
Units: mg Fe/g dw
arithmetic mean (standard deviation)	-7.1 ( 5.3 )	-6.7 ( 6.67 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until LPLV.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Deferasirox 5 mg/kg/day

Reporting group description

Reporting group title

Placebo/Deferasirox any dose

Reporting group description

Deferasirox/Placebo matched to deferasirox was administered in subjects daily through oral route.

Reporting group title

Deferasirox 10 mg/kg/day

Reporting group description

Serious adverse events	Deferasirox 5 mg/kg/day	Placebo/Deferasirox any dose	Deferasirox 10 mg/kg/day
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 55 (20.00%)	16 / 56 (28.57%)	12 / 55 (21.82%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 55 (1.82%)	1 / 56 (1.79%)	3 / 55 (5.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst ruptured
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
C-reactive protein
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ligament rupture
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus lesion
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Optic neuritis
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 55 (1.82%)	3 / 56 (5.36%)	2 / 55 (3.64%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolysis
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal tenderness
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	2 / 55 (3.64%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Portal vein thrombosis
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Babesiosis
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	3 / 55 (5.45%)	2 / 56 (3.57%)	4 / 55 (7.27%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Helicobacter gastritis
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 55 (0.00%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 55 (0.00%)	2 / 56 (3.57%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 55 (1.82%)	0 / 56 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 55 (0.00%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Deferasirox 5 mg/kg/day	Placebo/Deferasirox any dose	Deferasirox 10 mg/kg/day
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 55 (67.27%)	48 / 56 (85.71%)	45 / 55 (81.82%)
Investigations
Blood creatinine increased
subjects affected / exposed	1 / 55 (1.82%)	2 / 56 (3.57%)	3 / 55 (5.45%)
occurrences all number	1	2	6
Heart rate increased
subjects affected / exposed	0 / 55 (0.00%)	3 / 56 (5.36%)	0 / 55 (0.00%)
occurrences all number	0	5	0
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 55 (7.27%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences all number	4	2	0
Headache
subjects affected / exposed	3 / 55 (5.45%)	12 / 56 (21.43%)	11 / 55 (20.00%)
occurrences all number	10	21	33
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 55 (10.91%)	3 / 56 (5.36%)	4 / 55 (7.27%)
occurrences all number	7	3	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 55 (3.64%)	3 / 56 (5.36%)	1 / 55 (1.82%)
occurrences all number	2	6	1
Fatigue
subjects affected / exposed	3 / 55 (5.45%)	6 / 56 (10.71%)	7 / 55 (12.73%)
occurrences all number	4	8	8
Oedema peripheral
subjects affected / exposed	1 / 55 (1.82%)	4 / 56 (7.14%)	1 / 55 (1.82%)
occurrences all number	1	6	1
Pain
subjects affected / exposed	3 / 55 (5.45%)	1 / 56 (1.79%)	0 / 55 (0.00%)
occurrences all number	3	2	0
Pyrexia
subjects affected / exposed	10 / 55 (18.18%)	15 / 56 (26.79%)	5 / 55 (9.09%)
occurrences all number	11	22	5
Eye disorders
Conjunctivitis
subjects affected / exposed	3 / 55 (5.45%)	1 / 56 (1.79%)	1 / 55 (1.82%)
occurrences all number	3	1	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	4 / 55 (7.27%)	9 / 56 (16.07%)	4 / 55 (7.27%)
occurrences all number	5	13	4
Abdominal pain upper
subjects affected / exposed	4 / 55 (7.27%)	7 / 56 (12.50%)	9 / 55 (16.36%)
occurrences all number	6	7	10
Constipation
subjects affected / exposed	0 / 55 (0.00%)	3 / 56 (5.36%)	0 / 55 (0.00%)
occurrences all number	0	3	0
Diarrhoea
subjects affected / exposed	8 / 55 (14.55%)	12 / 56 (21.43%)	7 / 55 (12.73%)
occurrences all number	11	17	23
Dyspepsia
subjects affected / exposed	1 / 55 (1.82%)	2 / 56 (3.57%)	3 / 55 (5.45%)
occurrences all number	2	2	4
Food poisoning
subjects affected / exposed	0 / 55 (0.00%)	4 / 56 (7.14%)	3 / 55 (5.45%)
occurrences all number	0	5	3
Gastritis
subjects affected / exposed	3 / 55 (5.45%)	2 / 56 (3.57%)	1 / 55 (1.82%)
occurrences all number	3	2	1
Nausea
subjects affected / exposed	5 / 55 (9.09%)	12 / 56 (21.43%)	9 / 55 (16.36%)
occurrences all number	7	13	13
Tooth disorder
subjects affected / exposed	0 / 55 (0.00%)	3 / 56 (5.36%)	0 / 55 (0.00%)
occurrences all number	0	3	0
Vomiting
subjects affected / exposed	4 / 55 (7.27%)	8 / 56 (14.29%)	3 / 55 (5.45%)
occurrences all number	5	8	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 55 (5.45%)	8 / 56 (14.29%)	4 / 55 (7.27%)
occurrences all number	3	9	4
Dyspnoea
subjects affected / exposed	1 / 55 (1.82%)	3 / 56 (5.36%)	1 / 55 (1.82%)
occurrences all number	1	3	1
Epistaxis
subjects affected / exposed	3 / 55 (5.45%)	0 / 56 (0.00%)	1 / 55 (1.82%)
occurrences all number	3	0	1
Oropharyngeal pain
subjects affected / exposed	4 / 55 (7.27%)	3 / 56 (5.36%)	7 / 55 (12.73%)
occurrences all number	6	3	7
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	3 / 55 (5.45%)	5 / 56 (8.93%)	6 / 55 (10.91%)
occurrences all number	5	5	6
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 55 (1.82%)	4 / 56 (7.14%)	3 / 55 (5.45%)
occurrences all number	1	5	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 55 (5.45%)	5 / 56 (8.93%)	2 / 55 (3.64%)
occurrences all number	3	6	2
Back pain
subjects affected / exposed	2 / 55 (3.64%)	6 / 56 (10.71%)	1 / 55 (1.82%)
occurrences all number	2	7	1
Flank pain
subjects affected / exposed	1 / 55 (1.82%)	3 / 56 (5.36%)	0 / 55 (0.00%)
occurrences all number	1	5	0
Pain in extremity
subjects affected / exposed	2 / 55 (3.64%)	3 / 56 (5.36%)	2 / 55 (3.64%)
occurrences all number	3	3	2
Infections and infestations
Gastroenteritis
subjects affected / exposed	3 / 55 (5.45%)	4 / 56 (7.14%)	5 / 55 (9.09%)
occurrences all number	3	5	5
Gastroenteritis viral
subjects affected / exposed	0 / 55 (0.00%)	2 / 56 (3.57%)	3 / 55 (5.45%)
occurrences all number	0	2	3
Influenza
subjects affected / exposed	4 / 55 (7.27%)	5 / 56 (8.93%)	6 / 55 (10.91%)
occurrences all number	8	5	8
Nasopharyngitis
subjects affected / exposed	6 / 55 (10.91%)	6 / 56 (10.71%)	5 / 55 (9.09%)
occurrences all number	14	9	6
Pharyngitis
subjects affected / exposed	6 / 55 (10.91%)	2 / 56 (3.57%)	2 / 55 (3.64%)
occurrences all number	11	2	3
Rhinitis
subjects affected / exposed	2 / 55 (3.64%)	3 / 56 (5.36%)	5 / 55 (9.09%)
occurrences all number	3	4	5
Tonsillitis
subjects affected / exposed	5 / 55 (9.09%)	5 / 56 (8.93%)	3 / 55 (5.45%)
occurrences all number	7	10	3
Upper respiratory tract infection
subjects affected / exposed	9 / 55 (16.36%)	14 / 56 (25.00%)	14 / 55 (25.45%)
occurrences all number	12	27	28
Viral infection
subjects affected / exposed	2 / 55 (3.64%)	4 / 56 (7.14%)	0 / 55 (0.00%)
occurrences all number	2	5	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 55 (5.45%)	3 / 56 (5.36%)	1 / 55 (1.82%)
occurrences all number	4	3	1

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Were there any global substantial amendments to the protocol? Yes

10 Jun 2009

The purpose of this local amendment was to be in accordance with Greek National Ethical Committee which approved the clinical study protocol “under the condition that persons participating in the study are non-transfusion-dependent and over 18 years old”. Therefore the population criteria and the first inclusion criteria were modified to only allow inclusion of patients over 18 years old. Moreover, the collection of an additional blood sample for UGT1A1 genotyping was defined in original protocol part 7.6.6 was not performed in Greek patients. Finally, according to Greek Law, the modalities of the contracted convention insurance for the cover of responsibility of Researcher and Sponsor were to be reported in the protocol, section 11 “Administrative procedures”, provided in Appendix 16.1.1.

14 Aug 2009

The purpose of this amendment was to: • Allow dose adjustment after 6 months to study the impact of a dose increase in patients who may have required higher doses of deferasirox to reduce a high iron burden or to compensate for a high rate of gastrointestinal iron intake based on the following criterion : • Patients with a LIC >7 mg Fe/g dw after 6 months of treatment and with a LIC reduction by less than 15% compared to baseline had their treatment dose doubled • Patients with a LIC >7 mg Fe/g dw after 6 months of treatment and with a LIC reduction by 15% or more compared to baseline kept the same dose of treatment • Patients with a LIC equal to or lower than 7 mg stayed on the same dose • The wording of the primary objective was changed to reflect the amended treatment regimens • A description of a supportive analysis was added to the primary objective • Other objectives were replaced with secondary objectives • Exclusion criteria were added, deleted or modified: • to allow patients with a known lifetime history of transfusion in excess of 20 PRBC • to exclude patients for whom phlebotomy can be indicated • to exclude patients with ALT > 5 ULN (previously ALT > 3 ULN) • to exclude patients with urine protein/urine creatinine ratio > 1.0 mg/mg (previously urine protein/urine creatinine ratio > 0.5 mg/mg) • to exclude patients who received chelation within 1 month (previously 6 months) • to exclude patients with a history of drug or alcohol abuse within 12 months prior to enrollment • To modify the upper limit of liver enzymes (from 3xULN to 5xULN) in the “definition of notable ranges for laboratory tests” • LIC in the treatment stopping rule has been changed from <2 mg Fe /g dw to <3 mg Fe/g dw • To add an algorithm to manage gastrointestinal disturbances due to the investigational treatment • To update the protocol provided in Appendix 16.1.1. (“Other concomitant medications”) to be consistent Exjade® label

14 Aug 2009

CONTINUED: To update the informed consent form to reflect the changes of the amendment and to add the following : (1) a new heading "Contacts" as the last section after "Pregnancy" (2) a paragraph on emergency testing in instances of occupational blood exposure in the section "Risks and inconveniences" as follow-up action to an audit by the Food and Drug Administration • To update the visit schedule assessment as follows: • To delete “ Hematology/blood chemistry/iron metabolism” at Visit 3 • To check “Relevant medical history/current medical condition” also at screening visit 2 • To ensure that a pregnancy test is performed on all women with childbearing potential within 48 hours before first drug administration. If serum pregnancy test was done more than 48 hours before visit 3, an additional urinary pregnancy test was to be performed at Visit 3 • Weekly serum creatinine assessments were added to the patients who receive dose escalation at 6 months • To allow patient to be re-screened after 3 months when LIC and/or serum ferritin were below eligibility criteria, when ALT was above the eligibility criterion, or when urine protein/urine creatinine ratio was above the eligibility criterion. • To make it known that any patients participating in clinical study ICL670A2209 would be offered to continue in an open-label study extension. • To add the brand name THALASSA to the title of the study following the Novartis branding initiative.

13 Oct 2009

The purpose of this amendment was to include a one-year extension study to study CICL670A2209.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Liver Iron Concentration (LIC) from baseline to week 52

Primary: Change in Liver Iron Concentration (LIC) from baseline to week 52

Primary: LIC responses by the end of the extension phase

Primary: LIC responses by the end of the extension phase

Secondary: Change in Liver Iron Concentration (LIC) from baseline to Week 24

Secondary: Change in Liver Iron Concentration (LIC) from baseline to Week 24

Secondary: Change in serum ferritin from baseline to second and fourth quarter

Secondary: Change in serum ferritin from baseline to second and fourth quarter

Secondary: Change in Liver Iron Concentration (LIC) from baseline to Week 24 and to Week 52 in subjects with escalated dose after Week 24

Secondary: Change in Liver Iron Concentration (LIC) from baseline to Week 24 and to Week 52 in subjects with escalated dose after Week 24

Secondary: Correlation between Serum Ferritin and LIC (Liver Iron Concentration)

Secondary: Correlation between Serum Ferritin and LIC (Liver Iron Concentration)

Secondary: Change in haemoglobin absolute levels from baseline to Week 52 and Month 24

Secondary: Change in haemoglobin absolute levels from baseline to Week 52 and Month 24

Secondary: Change in transferrin saturation levels from baseline to Week 52 and Month 24

Secondary: Change in transferrin saturation levels from baseline to Week 52 and Month 24

Secondary: Absolute change in liver iron concentration (LIC) in placebo treated subjects from baseline to Week 52

Secondary: Absolute change in liver iron concentration (LIC) in placebo treated subjects from baseline to Week 52

Secondary: Absolute change in serum ferritin from baseline to eighth quarter

Secondary: Absolute change in serum ferritin from baseline to eighth quarter

Secondary: Absolute change in LIC for subjects who stopped deferasirox treatment

Secondary: Absolute change in LIC for subjects who stopped deferasirox treatment

Secondary: Change in Liver Iron Concentration (LIC) from baseline Month 24

Secondary: Change in Liver Iron Concentration (LIC) from baseline Month 24

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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