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    Clinical Trial Results:
    A multicenter, randomized, open-label phase II trial evaluating deferasirox compared with deferoxamine in patients with cardiac iron overload due to chronic blood transfusions (CORDELIA) Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2007-000766-20
    Trial protocol
    		 GB   IT  
    Global end of trial date
    05 Mar 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2018
    First version publication date
    15 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CICL670A2206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00600938
    WHO universal trial number (UTN)
    		 -
    Sponsors
    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 ,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Mar 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the efficacy of deferasirox, compared to deferoxamine in subjects with cardiac iron overload due to chronic blood transfusions by using T2-star (T2*) technique for measurement of iron in tissue after a treatment period of 12 months (core study) and to collect additional data on efficacy of deferasirox and deferoxamine when treated for more than 12 months (extension study).
    Protection of trial subjects
    No rescue medication was allowed in the study.
    Background therapy
    		 Regular medications required to treat concomitant medical conditions were allowed during the study. Subjects also continued blood transfusions according to the regimen that they had been receiving prior to enrollment to maintain a haemoglobin level of 9 gram/decilitre (g/dL).
    Evidence for comparator
    		 Deferoxamine mesylate (DFO), is standard of care for treating transfusional myocardial iron overload, including severe cardiac iron overload. Hence, DFO was selected as the active comparator and administered via subcutaneous (s.c.) infusion over 8 to 10 hours, at least 5 days per week.
    Actual start date of recruitment
    26 Nov 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 26
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Cyprus: 6
    Country: Number of subjects enrolled
    United Arab Emirates: 20
    Country: Number of subjects enrolled
    Egypt: 44
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Lebanon: 5
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Thailand: 19
    Country: Number of subjects enrolled
    Turkey: 60
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    197
    EEA total number of subjects
    12
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    12
    Adolescents (12-17 years)
    69
    Adults (18-64 years)
    116
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 22 centres in 11 countries.

    Pre-assignment
    Screening details
    		 A total of 925 subjects were screened, 728 were screen failures and remaining 197 subjects were randomized into the core study. Of the 160 subjects who completed the core study, 146 subjects were enrolled to extension study.

    Period 1
    Period 1 title
    Core Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Investigators and subjects were not blinded but in order to minimize the potential impact of treatment, Central reader, Independent reader, Adjudicator, Central Imaging Contract Research Organization Technical and Medical Quality Readers and Novartis clinical team were blinded to the treatment allocation until database lock for the primary analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Deferasirox (ICL)
    Arm description
    		 Subjects received deferasirox as 20 milligram (mg)/kilogram (kg)/day once daily (od) for 2 weeks, followed by 30 mg/kg/day od for 1 week and a subsequent continuation of 40 mg/kg/day od as target dose. Deferasirox was administered every morning 30 minutes before breakfast. In subjects with gastro-intestinal symptoms required twice daily (bid) administration, the first half of the daily dose was provided in morning and remaining half was provided in the evening.
    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 tablets were orally administered as 20 mg/kg/day for 2 weeks, followed by 30 mg/kg/day for 1 week and a subsequent continuation of 40 mg/kg/day as a target dose.

    Arm title
    		 Deferoxamine (DFO)
    Arm description
    		 Deferoxamine mesylate was infused via s.c. route as target dose of 50 mg/kg/day to 60 mg/kg/day in 8 to 12 hour intervals administered 5 to 7 days/week.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Deferoxamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Deferoxamine was infused via s.c. route as target dose of 50 mg/kg/day to 60 mg/kg/day in 8 to 12 hour intervals administered 5 to 7 days/week.

    Number of subjects in period 1
    		Deferasirox (ICL) Deferoxamine (DFO)
    Started
    98
    99
    Completed
    82
    78
    Not completed
    16
    21
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    7
    12
         Unsatisfactory therapeutic effect
    1
    2
         Lost to follow-up
    3
    2
         Abnormal test procedure result
    3
    2
         Protocol deviation
    1
    2
    Period 2
    Period 2 title
    Extension Study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Investigators and subjects were not blinded but in order to minimize the potential impact of treatment, Central reader, Independent reader and Adjudicator were blinded to the treatment allocation during the extension phase.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Deferasirox (ICL to ICL)
    Arm description
    		 Subjects who received deferasirox in both core and extension study.
    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 tablets were orally administered as 20 mg/kg/day for 2 weeks, followed by 30 mg/kg/day for 1 week and a subsequent continuation of 40 mg/kg/day as a target dose.

    Arm title
    		 Deferoxamine (DFO to DFO)
    Arm description
    		 Subjects who received deferoxamine in both core and extension study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Deferoxamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Deferoxamine was infused via s.c. route as target dose of 50 mg/kg/day to 60 mg/kg/day in 8 to 12 hour intervals administered 5 to 7 days/week.

    Arm title
    		 Deferoxamine to Deferasirox (DFO to ICL)
    Arm description
    		 Subjects who received deferoxamine in core study, but received deferasirox in extension study.
    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 tablets were orally administered as 20 mg/kg/day for 2 weeks, followed by 30 mg/kg/day for 1 week and a subsequent continuation of 40 mg/kg/day as a target dose.

    Arm title
    		 Deferasirox to Deferoxamine (ICL to DFO)
    Arm description
    		 Subjects who received deferasirox in core study but received deferoxamine in extension study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Deferoxamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Deferoxamine was infused via s.c. route as target dose of 50 mg/kg/day to 60 mg/kg/day in 8 to 12 hour intervals administered 5 to 7 days/week.

    Number of subjects in period 2 [1]
    		Deferasirox (ICL to ICL) Deferoxamine (DFO to DFO) Deferoxamine to Deferasirox (DFO to ICL) Deferasirox to Deferoxamine (ICL to DFO)
    Started
    74
    29
    42
    1
    Completed
    65
    24
    33
    0
    Not completed
    9
    5
    9
    1
         Adverse event, serious fatal
    1
    -
    -
    -
         Consent withdrawn by subject
    2
    2
    3
    -
         Adverse event, non-fatal
    1
    -
    2
    -
         Unsatisfactory therapeutic effect
    4
    1
    1
    -
         Lost to follow-up
    1
    1
    2
    -
         Abnormal test procedure result(s)
    -
    1
    1
    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: Of 160 subjects who completed the preceding period, only 146 subjects opted to enroll in extension study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Deferasirox (ICL)
    Reporting group description
    		 Subjects received deferasirox as 20 milligram (mg)/kilogram (kg)/day once daily (od) for 2 weeks, followed by 30 mg/kg/day od for 1 week and a subsequent continuation of 40 mg/kg/day od as target dose. Deferasirox was administered every morning 30 minutes before breakfast. In subjects with gastro-intestinal symptoms required twice daily (bid) administration, the first half of the daily dose was provided in morning and remaining half was provided in the evening.

    Reporting group title
    Deferoxamine (DFO)
    Reporting group description
    		 Deferoxamine mesylate was infused via s.c. route as target dose of 50 mg/kg/day to 60 mg/kg/day in 8 to 12 hour intervals administered 5 to 7 days/week.

    Reporting group values
    		 Deferasirox (ICL) Deferoxamine (DFO) Total
    Number of subjects
    		 98 99 197
    Age categorical
    Units: Subjects
        Children and Adolescents (10-<18)
    		 40 41 81
        Adults (18-<50)
    		 58 58 116
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 19.9 ( 6.53 ) 19.7 ( 6.32 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 57 115
        Male
    		 40 42 82

    End points

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    End points reporting groups
    Reporting group title
    Deferasirox (ICL)
    Reporting group description
    		 Subjects received deferasirox as 20 milligram (mg)/kilogram (kg)/day once daily (od) for 2 weeks, followed by 30 mg/kg/day od for 1 week and a subsequent continuation of 40 mg/kg/day od as target dose. Deferasirox was administered every morning 30 minutes before breakfast. In subjects with gastro-intestinal symptoms required twice daily (bid) administration, the first half of the daily dose was provided in morning and remaining half was provided in the evening.

    Reporting group title
    Deferoxamine (DFO)
    Reporting group description
    		 Deferoxamine mesylate was infused via s.c. route as target dose of 50 mg/kg/day to 60 mg/kg/day in 8 to 12 hour intervals administered 5 to 7 days/week.
    Reporting group title
    Deferasirox (ICL to ICL)
    Reporting group description
    		 Subjects who received deferasirox in both core and extension study.

    Reporting group title
    Deferoxamine (DFO to DFO)
    Reporting group description
    		 Subjects who received deferoxamine in both core and extension study.

    Reporting group title
    Deferoxamine to Deferasirox (DFO to ICL)
    Reporting group description
    		 Subjects who received deferoxamine in core study, but received deferasirox in extension study.

    Reporting group title
    Deferasirox to Deferoxamine (ICL to DFO)
    Reporting group description
    		 Subjects who received deferasirox in core study but received deferoxamine in extension study.

    Primary: Core Study: Change from baseline in cardiac iron content as measured by Myocardial T2* at Month 12

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    End point title
    		 Core Study: Change from baseline in cardiac iron content as measured by Myocardial T2* at Month 12
    End point description
    Magnetic resonance (MR) T2-star (T2*) technique was used to measure tissue iron in cardiac iron overload condition. The ratio of cardiac iron concentration was measured as T2* after 12 months of study treatment divided by the T2* value at baseline. A T2* 10-20 milliseconds (ms) indicates mild/moderate cardiac iron overload, and a T2* less than (<) 10 ms indicates severe cardiac iron overload. Cardiovascular Magnetic Resonance (CMR) was utilized to evaluate the effects of chelation therapy with ICL or DFO on cardiac iron concentration. The primary analysis was performed in Per-Protocol Set (PPS), defined as all randomized subjects who received study treatment for at least 6 months and had no major protocol violations.
    End point type
    Primary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    91
    81
    Units: Ratio
        geometric mean (confidence interval 95%)
    1.12 (1.07 to 1.18)
    1.07 (1.02 to 1.11)
    Statistical analysis title
    		 Change in myocardial T2* from baseline at Month 12
    Statistical analysis description
    The analysis was performed to show non-inferiority in efficacy of ICL compared to DFO in treating cardiac iron overload measured by T2*. According to null hypothesis, pre-specified non-inferiority margin of 0.9, was applied to the geometric mean ratio.
    Comparison groups
    Deferasirox (ICL) v Deferoxamine (DFO)
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.0567 [2]
    Method
    		 Stagewise ordering method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.0557
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9981
         upper limit
    		 1.1331
    Notes
    [1] - As non-inferiority of deferasirox was established, a superiority test was performed by comparing the lower limit of the repeated confidence interval (CI) to 0 which corresponds to a ratio of 100%.
    [2] - P-value was based on the Tsiatis, Rosner and Mehta stagewise ordering testing.

    Secondary: Core Study: Absolute change from baseline in Left Ventricular Ejection Fraction (LVEF) at Month 12

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    End point title
    		 Core Study: Absolute change from baseline in Left Ventricular Ejection Fraction (LVEF) at Month 12
    End point description
    Left Ventricular Ejection Fraction (LVEF) was defined as the fraction of blood pumped out of the heart’s left ventricular chamber with each heartbeat, and was a measure of cardiac output for the heart. LVEF assessment was based on CMR echocardiography. The normal fraction of ejection was more than (>)55%. The analysis was performed in PPS population.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    91
    81
    Units: Percentage of LVEF
        least squares mean (standard error)
    -0.5 ( 0.47 )
    0 ( 0.49 )
    No statistical analyses for this end point

    Secondary: Core Study: Change from baseline in Left Ventricular Ejection Fraction (LVEF) at Month 6

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    End point title
    		 Core Study: Change from baseline in Left Ventricular Ejection Fraction (LVEF) at Month 6
    End point description
    LVEF was defined as the fraction of blood pumped out of the heart’s left ventricular chamber with each heartbeat, and was a measure of cardiac output for the heart. LVEF assessment was based on CMR echocardiography. The normal fraction of ejection was >55%. The analysis was performed in PPS population.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    85
    73
    Units: Percentage of LVEF
        arithmetic mean (standard deviation)
    -0.95 ( 4.485 )
    -0.37 ( 4.389 )
    No statistical analyses for this end point

    Secondary: Core Study: Change from baseline in cardiac iron content as measured by Myocardial T2* at Month 6

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    End point title
    		 Core Study: Change from baseline in cardiac iron content as measured by Myocardial T2* at Month 6
    End point description
    Myocardial T2* technique was used to measure tissue iron in cardiac iron overload condition. The ratio of cardiac iron concentration was measured as T2* after 12 months of study treatment divided by the T2* value at baseline. A T2* 10-20 ms indicates mild/moderate cardiac iron overload, and a T2* <10 ms indicates severe cardiac iron overload. CMR was utilized to evaluate the effects of chelation therapy with ICL or DFO on cardiac iron concentration. The analysis was performed in the PPS population.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    85
    73
    Units: Ratio
        geometric mean (confidence interval 95%)
    1.04 (1 to 1.08)
    1.04 (1 to 1.08)
    No statistical analyses for this end point

    Secondary: Core Study: Change from baseline in Left Ventricular End Systolic Volume Index (LVESVI) at Month 6 and Month 12

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    End point title
    		 Core Study: Change from baseline in Left Ventricular End Systolic Volume Index (LVESVI) at Month 6 and Month 12
    End point description
    Left Ventricular End Systolic Volume Index (LVESVI) was defined as the volume of blood in the heart’s left ventricular chamber at the end of the heart’s contraction indexed to body surface area . LVESV assessment was based on CMR echocardiography. The analysis was performed in the PPS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    91
    81
    Units: millilitre(s)/square meter
    arithmetic mean (standard deviation)
        Change from baseline at 6 Month (n= 85, 73)
    1.8 ( 8.021 )
    0.88 ( 8.919 )
        Change from baseline at 12 Month(n= 70, 67)
    1.8 ( 8.342 )
    -0.01 ( 10.463 )
    No statistical analyses for this end point

    Secondary: Core Study: Change from baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) at Month 6 and Month 12

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    End point title
    		 Core Study: Change from baseline in Left Ventricular End Diastolic Volume Index (LVEDVI) at Month 6 and Month 12
    End point description
    Left Ventricular End Diastolic Volume Index (LVEDVI) was defined as the volume of blood in the heart’s left ventricular chamber at the beginning of filling with blood indexed to body surface area. LVEDV assessment was based on CMR echocardiography. The analysis was performed in the PPS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    91
    81
    Units: millilitre(s)/square meter
    arithmetic mean (standard deviation)
        Change from Baseline at 6 Month (n= 85, 73)
    1.81 ( 14.515 )
    1.48 ( 19.188 )
        Change from Baseline at 12 Month (n= 70, 67)
    2.27 ( 12.787 )
    0.76 ( 20.166 )
    No statistical analyses for this end point

    Secondary: Core Study: Change in Left Ventricular Mass Index (LVMI) at Month 6 and Month 12

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    End point title
    		 Core Study: Change in Left Ventricular Mass Index (LVMI) at Month 6 and Month 12
    End point description
    Left ventricular mass index (LVMI) was defined as left ventricular mass indexed by the body surface area. The LVM was calculated as left ventricular muscle volume multiplied by myocardial density. LVMI assessment was based on CMR echocardiography. The analysis was performed in the PPS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    91
    81
    Units: gram(s)/square meter
    arithmetic mean (standard deviation)
        Change from Baseline at 6 Month (n= 85, 73)
    1.01 ( 13.102 )
    3.32 ( 13.585 )
        Change from Baseline at 12 Month (n= 70, 67)
    4.36 ( 13.18 )
    5.51 ( 15.434 )
    No statistical analyses for this end point

    Secondary: Core Study: Percentage of subjects who discontinued due to cardiac dysfunction at Month 12

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    End point title
    		 Core Study: Percentage of subjects who discontinued due to cardiac dysfunction at Month 12
    End point description
    Cardiac dysfunction was defined as clinical symptoms of shortness of breath at rest or exertion, orthopnea, exercise intolerance, lower extremity edema, arrythmias. Subjects who withdrew from the study due to following cardiac parameters: LVEF <50%, T2* <6 ms or significant decreases in T2* ≥33% from baseline. The analysis was performed in the FAS population defined as all subjects who received at least one dose of study treatment and had at least one post ­baseline assessment for primary efficacy..
    End point type
    Secondary
    End point timeframe
    12 Month
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    98
    99
    Units: Percentage of subjects
        number (not applicable)
    3.1
    2
    No statistical analyses for this end point

    Secondary: Core Study: Number of subjects with adverse events, serious adverse events and death

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    End point title
    		 Core Study: Number of subjects with adverse events, serious adverse events and death
    End point description
    An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing the informed consent even if the event is not considered to be related to the study drug(s). Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms, are considered clinically significant or require therapy. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. Death was defined as a fatal event leading to permanent cessation of all vital functions of the body.
    End point type
    Secondary
    End point timeframe
    From start of study treatment to Month 12
    End point values
    		 Deferasirox (ICL) Deferoxamine (DFO)
    Number of subjects analysed
    96
    91
    Units: Number of subjects
        AEs
    65
    69
        SAEs
    10
    10
        Death
    1
    1
    No statistical analyses for this end point

    Secondary: Core Study: Area under the plasma concentration-time curve (AUCtau) of deferasirox

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    End point title
    		 Core Study: Area under the plasma concentration-time curve (AUCtau) of deferasirox [3]
    End point description
    The AUCtau was defined as area under the plasma concentration-time curve from time zero to dosing interval, calculated by a trapezoidal method. The analysis was performed in the Pharmacokinetics Analysis Set (PAS) defined as subjects who received the same dose of deferasirox for at least four consecutive days prior to PK sample collection and completed PK sample collection.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour, 2 hour and 4 hour post-dose
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic evaluation was planned for study drug only.  
    End point values
    		 Deferasirox (ICL)
    Number of subjects analysed
    13
    Units: hours*nanograms/milliliters
        arithmetic mean (standard deviation)
    2129.7 ( 930.202 )
    No statistical analyses for this end point

    Secondary: Core Study: Maximum Plasma Concentration (Cmax) of deferasirox

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    End point title
    		 Core Study: Maximum Plasma Concentration (Cmax) of deferasirox [4]
    End point description
    Maximum plasma concentration (Cmax) was defined as the peak plasma level of deferasirox, derived from plasma concentration-time data of deferasirox. The analysis was performed in the PAS population.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour, 2 hour and 4 hour post-dose
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic evaluation was planned for study drug only.  
    End point values
    		 Deferasirox (ICL)
    Number of subjects analysed
    13
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    150.09 ( 59.143 )
    No statistical analyses for this end point

    Secondary: Core Study: Plasma concentration of deferasirox

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    End point title
    		 Core Study: Plasma concentration of deferasirox [5]
    End point description
    Amount of deferasirox present in plasma was determined. The analysis was performed in the PAS population. The'n' signifies those subjects evaluable for this measure at the specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour, 2 hour and 4 hour post-dose
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic evaluation was planned for study drug only.  
    End point values
    		 Deferasirox (ICL)
    Number of subjects analysed
    15
    Units: micromole(s)/litre
    arithmetic mean (standard deviation)
        1 hour (n= 15)
    96.32 ( 35.799 )
        2 hour (n= 15)
    136.47 ( 51.831 )
        4 hour (n= 13)
    133.33 ( 62.815 )
    No statistical analyses for this end point

    Secondary: Core Study: Time to Maximum Plasma Concentration (Tmax) of deferasirox

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    End point title
    		 Core Study: Time to Maximum Plasma Concentration (Tmax) of deferasirox [6]
    End point description
    Tmax was defined as the time taken to reach the maximum plasma concentration. The analysis was performed on the PAS population.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1 hour, 2 hour and 4 hour post-dose
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic evaluation was planned for study drug only.  
    End point values
    		 Deferasirox (ICL)
    Number of subjects analysed
    13
    Units: hour
        median (full range (min-max))
    4 (1 to 4)
    No statistical analyses for this end point

    Secondary: Extension Study: Change from baseline in cardiac iron content as measured by Myocardial T2* at Month 24

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    End point title
    		 Extension Study: Change from baseline in cardiac iron content as measured by Myocardial T2* at Month 24
    End point description
    Myocardial T2* technique was used to measure tissue iron in cardiac iron overload condition. The ratio of cardiac iron concentration was measured as T2* after 12 months of study treatment divided by the T2* value at baseline. A T2* 10-20 ms indicates mild/moderate cardiac iron overload, and a T2* <10 ms indicates severe cardiac iron overload. CMR was utilized to evaluate the effects of chelation therapy with ICL or DFO on cardiac iron concentration. The analysis was performed in the FAS population defined as all subjects who received at least one dose of study treatment and had at least one post-baseline assessment for primary efficacy. Here, "Number of subjects analysed" signifies those subjects who were evaluable for this outcome measure. The value -99999.9 and 99999.9 in the data field represents not available data because EudraCT system is not allowing user to enter "NA" or leave the measure dispersion data field blank where only one patient was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Core study), Months 24 (Core + Extension study)
    End point values
    		 Deferasirox (ICL to ICL) Deferoxamine (DFO to DFO) Deferoxamine to Deferasirox (DFO to ICL) Deferasirox to Deferoxamine (ICL to DFO)
    Number of subjects analysed
    63
    25
    33
    1 [7]
    Units: Ratio
        geometric mean (confidence interval 95%)
    1.38 (1.28 to 1.49)
    1.33 (1.13 to 1.55)
    1.21 (1.09 to 1.34)
    1.11 (-99999.9 to 99999.9)
    Notes
    [7] - Only 1 patient, hence no dispersion data. System does not allow to put NA or to leave it blank.
    No statistical analyses for this end point

    Secondary: Extension Study: Absolute change from baseline in Left Ventricular Ejection Fraction (LVEF) at Month 24

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    End point title
    		 Extension Study: Absolute change from baseline in Left Ventricular Ejection Fraction (LVEF) at Month 24
    End point description
    LVEF was defined as the fraction of blood pumped out of the heart’s left ventricular chamber with each heartbeat, and was a measure of cardiac output for the heart. LVEF assessment was based on CMR echocardiography. The normal fraction of ejection was >55%. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies those subjects who were evaluable for this outcome measure. The value '0' in the standard deviation data field represents not available data because EudraCT system is not allowing user to enter "NA" or leave the measure dispersion data field blank where only one patient was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Core study), Months 24 (Core + Extension study)
    End point values
    		 Deferasirox (ICL to ICL) Deferoxamine (DFO to DFO) Deferoxamine to Deferasirox (DFO to ICL) Deferasirox to Deferoxamine (ICL to DFO)
    Number of subjects analysed
    63
    25
    33
    1 [8]
    Units: Percentage of LVEF
        arithmetic mean (standard deviation)
    0.6 ( 4.72 )
    -0.6 ( 5.02 )
    0.2 ( 4.82 )
    -18 ( 0 )
    Notes
    [8] - Standard deviation value (0) denotes not applicable, as only one subject was analysed.
    No statistical analyses for this end point

    Secondary: Extension Study: Change from baseline in Left Ventricular End Systolic Volume Indices (LVESVI) at Month 24

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    End point title
    		 Extension Study: Change from baseline in Left Ventricular End Systolic Volume Indices (LVESVI) at Month 24
    End point description
    LVESVI was defined as the volume of blood in the heart’s left ventricular chamber at the end of the heart’s contraction indexed to body surface area. LVESV assessment was based on CMR echocardiography. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Core study), Months 24 (Core + Extension study)
    End point values
    		 Deferasirox (ICL to ICL) Deferoxamine (DFO to DFO) Deferoxamine to Deferasirox (DFO to ICL) Deferasirox to Deferoxamine (ICL to DFO)
    Number of subjects analysed
    60
    23
    33
    0 [9]
    Units: millilitre(s)/square meter
        arithmetic mean (standard deviation)
    1.6 ( 10.21 )
    4.3 ( 8.66 )
    1.7 ( 8.56 )
    ( )
    Notes
    [9] - No subject was evaluable at this time point.
    No statistical analyses for this end point

    Secondary: Extension Study: Change from baseline in Left Ventricular End Diastolic Volume Indices (LVEDVI) at Month 24

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    End point title
    		 Extension Study: Change from baseline in Left Ventricular End Diastolic Volume Indices (LVEDVI) at Month 24
    End point description
    LVEDVI was defined as the volume of blood in the heart’s left ventricular chamber at the beginning of the chamber’s filling with blood indexed to body surface area. LVEDV assessment was based on CMR echocardiography. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Core study), Months 24 (Core + Extension study)
    End point values
    		 Deferasirox (ICL to ICL) Deferoxamine (DFO to DFO) Deferoxamine to Deferasirox (DFO to ICL) Deferasirox to Deferoxamine (ICL to DFO)
    Number of subjects analysed
    60
    23
    33
    0 [10]
    Units: millilitre(s)/square meter
        arithmetic mean (standard deviation)
    3.4 ( 21.15 )
    9.5 ( 14.6 )
    5.4 ( 13.97 )
    ( )
    Notes
    [10] - No subject was evaluable at this time point.
    No statistical analyses for this end point

    Secondary: Extension Study: Change from baseline in Left Ventricular Mass Index (LVMI) at Month 24

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    End point title
    		 Extension Study: Change from baseline in Left Ventricular Mass Index (LVMI) at Month 24
    End point description
    Left ventricular mass index (LVMI) was defined as left ventricular mass indexed by the body surface area. The LVM was calculated as left ventricular muscle volume multiplied by myocardial density. LVMI assessment was based on CMR echocardiography. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Core study), Months 24 (Core + Extension study)
    End point values
    		 Deferasirox (ICL to ICL) Deferoxamine (DFO to DFO) Deferoxamine to Deferasirox (DFO to ICL) Deferasirox to Deferoxamine (ICL to DFO)
    Number of subjects analysed
    60
    23
    33
    0 [11]
    Units: gram(s)/square meter
        arithmetic mean (standard deviation)
    5.6 ( 13 )
    6.7 ( 14.96 )
    10.3 ( 13.32 )
    ( )
    Notes
    [11] - No subject was evaluable at this time point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Core ICL670
    Reporting group description
    		 Core ICL670

    Reporting group title
    Core DFO
    Reporting group description
    		 Core DFO

    Reporting group title
    Extension ICL to ICL
    Reporting group description
    		 Extension ICL to ICL

    Reporting group title
    Extension DFO to DFO
    Reporting group description
    		 Extension DFO to DFO

    Reporting group title
    Extension DFO to ICL
    Reporting group description
    		 Extension DFO to ICL

    Reporting group title
    Extension ICL to DFO
    Reporting group description
    		 Extension ICL to DFO

    Serious adverse events
    		 Core ICL670 Core DFO Extension ICL to ICL Extension DFO to DFO Extension DFO to ICL Extension ICL to DFO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 96 (10.42%)
    10 / 91 (10.99%)
    14 / 73 (19.18%)
    4 / 29 (13.79%)
    9 / 42 (21.43%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    1
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Grand mal convulsion
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypersplenism
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    1 / 29 (3.45%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 91 (1.10%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal rupture
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 91 (1.10%)
    1 / 73 (1.37%)
    1 / 29 (3.45%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    1 / 29 (3.45%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    1 / 29 (3.45%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypogonadism
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    1 / 29 (3.45%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    1 / 29 (3.45%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    1 / 29 (3.45%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Yersinia infection
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Calcium deficiency
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemosiderosis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    2 / 73 (2.74%)
    0 / 29 (0.00%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 91 (1.10%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron overload
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 91 (2.20%)
    2 / 73 (2.74%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Core ICL670 Core DFO Extension ICL to ICL Extension DFO to DFO Extension DFO to ICL Extension ICL to DFO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 96 (62.50%)
    58 / 91 (63.74%)
    56 / 73 (76.71%)
    19 / 29 (65.52%)
    36 / 42 (85.71%)
    1 / 1 (100.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 96 (1.04%)
    2 / 91 (2.20%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    5
    0
    Injection site reaction
         subjects affected / exposed
    0 / 96 (0.00%)
    3 / 91 (3.30%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    0
    5
    0
    0
    5
    0
    Pyrexia
         subjects affected / exposed
    5 / 96 (5.21%)
    5 / 91 (5.49%)
    6 / 73 (8.22%)
    3 / 29 (10.34%)
    5 / 42 (11.90%)
    1 / 1 (100.00%)
         occurrences all number
    6
    5
    11
    3
    8
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 96 (4.17%)
    2 / 91 (2.20%)
    5 / 73 (6.85%)
    0 / 29 (0.00%)
    2 / 42 (4.76%)
    0 / 1 (0.00%)
         occurrences all number
    4
    2
    5
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    4 / 96 (4.17%)
    3 / 91 (3.30%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    5
    5
    1
    0
    8
    0
    Nasal congestion
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 91 (1.10%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    6 / 96 (6.25%)
    2 / 91 (2.20%)
    6 / 73 (8.22%)
    0 / 29 (0.00%)
    5 / 42 (11.90%)
    1 / 1 (100.00%)
         occurrences all number
    6
    2
    6
    0
    7
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 96 (2.08%)
    1 / 91 (1.10%)
    4 / 73 (5.48%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    6
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 96 (9.38%)
    5 / 91 (5.49%)
    9 / 73 (12.33%)
    2 / 29 (6.90%)
    4 / 42 (9.52%)
    1 / 1 (100.00%)
         occurrences all number
    12
    5
    15
    2
    7
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 96 (7.29%)
    3 / 91 (3.30%)
    8 / 73 (10.96%)
    1 / 29 (3.45%)
    2 / 42 (4.76%)
    1 / 1 (100.00%)
         occurrences all number
    11
    3
    15
    1
    3
    3
    Blood creatinine increased
         subjects affected / exposed
    8 / 96 (8.33%)
    2 / 91 (2.20%)
    9 / 73 (12.33%)
    1 / 29 (3.45%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    8
    3
    12
    2
    6
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 91 (0.00%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 91 (1.10%)
    1 / 73 (1.37%)
    1 / 29 (3.45%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    1
    3
    0
    Platelet count increased
         subjects affected / exposed
    2 / 96 (2.08%)
    5 / 91 (5.49%)
    3 / 73 (4.11%)
    6 / 29 (20.69%)
    0 / 42 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    6
    6
    14
    0
    0
    Protein urine present
         subjects affected / exposed
    11 / 96 (11.46%)
    8 / 91 (8.79%)
    6 / 73 (8.22%)
    1 / 29 (3.45%)
    7 / 42 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    22
    11
    14
    1
    10
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 96 (0.00%)
    3 / 91 (3.30%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    0
    4
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 96 (5.21%)
    5 / 91 (5.49%)
    7 / 73 (9.59%)
    2 / 29 (6.90%)
    4 / 42 (9.52%)
    0 / 1 (0.00%)
         occurrences all number
    7
    10
    11
    3
    9
    0
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    0 / 96 (0.00%)
    4 / 91 (4.40%)
    1 / 73 (1.37%)
    2 / 29 (6.90%)
    2 / 42 (4.76%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    1
    2
    3
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 96 (1.04%)
    2 / 91 (2.20%)
    4 / 73 (5.48%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    4
    0
    3
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 96 (7.29%)
    2 / 91 (2.20%)
    7 / 73 (9.59%)
    1 / 29 (3.45%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    11
    2
    11
    1
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    5 / 96 (5.21%)
    5 / 91 (5.49%)
    6 / 73 (8.22%)
    3 / 29 (10.34%)
    5 / 42 (11.90%)
    0 / 1 (0.00%)
         occurrences all number
    10
    7
    11
    3
    7
    0
    Diarrhoea
         subjects affected / exposed
    12 / 96 (12.50%)
    4 / 91 (4.40%)
    10 / 73 (13.70%)
    0 / 29 (0.00%)
    9 / 42 (21.43%)
    1 / 1 (100.00%)
         occurrences all number
    16
    4
    20
    0
    13
    1
    Nausea
         subjects affected / exposed
    6 / 96 (6.25%)
    2 / 91 (2.20%)
    4 / 73 (5.48%)
    1 / 29 (3.45%)
    4 / 42 (9.52%)
    0 / 1 (0.00%)
         occurrences all number
    6
    2
    4
    1
    5
    0
    Vomiting
         subjects affected / exposed
    6 / 96 (6.25%)
    1 / 91 (1.10%)
    6 / 73 (8.22%)
    0 / 29 (0.00%)
    4 / 42 (9.52%)
    0 / 1 (0.00%)
         occurrences all number
    7
    1
    7
    0
    4
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 96 (4.17%)
    0 / 91 (0.00%)
    4 / 73 (5.48%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    5
    0
    1
    0
    Urticaria
         subjects affected / exposed
    3 / 96 (3.13%)
    3 / 91 (3.30%)
    4 / 73 (5.48%)
    3 / 29 (10.34%)
    2 / 42 (4.76%)
    0 / 1 (0.00%)
         occurrences all number
    3
    3
    4
    3
    3
    0
    Endocrine disorders
    Hypogonadism
         subjects affected / exposed
    2 / 96 (2.08%)
    2 / 91 (2.20%)
    0 / 73 (0.00%)
    0 / 29 (0.00%)
    2 / 42 (4.76%)
    1 / 1 (100.00%)
         occurrences all number
    2
    3
    0
    0
    5
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 96 (7.29%)
    4 / 91 (4.40%)
    5 / 73 (6.85%)
    2 / 29 (6.90%)
    2 / 42 (4.76%)
    1 / 1 (100.00%)
         occurrences all number
    12
    5
    14
    2
    4
    2
    Back pain
         subjects affected / exposed
    7 / 96 (7.29%)
    4 / 91 (4.40%)
    7 / 73 (9.59%)
    1 / 29 (3.45%)
    2 / 42 (4.76%)
    0 / 1 (0.00%)
         occurrences all number
    7
    4
    10
    1
    2
    0
    Osteoporosis
         subjects affected / exposed
    5 / 96 (5.21%)
    2 / 91 (2.20%)
    3 / 73 (4.11%)
    1 / 29 (3.45%)
    2 / 42 (4.76%)
    1 / 1 (100.00%)
         occurrences all number
    5
    2
    6
    2
    3
    2
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 96 (1.04%)
    3 / 91 (3.30%)
    1 / 73 (1.37%)
    1 / 29 (3.45%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    1
    3
    1
    1
    3
    0
    Bronchitis
         subjects affected / exposed
    1 / 96 (1.04%)
    3 / 91 (3.30%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    2
    4
    2
    0
    4
    0
    Influenza
         subjects affected / exposed
    10 / 96 (10.42%)
    6 / 91 (6.59%)
    11 / 73 (15.07%)
    1 / 29 (3.45%)
    7 / 42 (16.67%)
    0 / 1 (0.00%)
         occurrences all number
    10
    8
    17
    1
    11
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 96 (8.33%)
    4 / 91 (4.40%)
    12 / 73 (16.44%)
    1 / 29 (3.45%)
    6 / 42 (14.29%)
    0 / 1 (0.00%)
         occurrences all number
    10
    5
    18
    2
    6
    0
    Otitis media
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 91 (0.00%)
    1 / 73 (1.37%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    Pharyngitis
         subjects affected / exposed
    3 / 96 (3.13%)
    2 / 91 (2.20%)
    4 / 73 (5.48%)
    0 / 29 (0.00%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    4
    2
    5
    0
    3
    0
    Tonsillitis
         subjects affected / exposed
    1 / 96 (1.04%)
    2 / 91 (2.20%)
    4 / 73 (5.48%)
    1 / 29 (3.45%)
    3 / 42 (7.14%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    4
    1
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 96 (8.33%)
    8 / 91 (8.79%)
    13 / 73 (17.81%)
    1 / 29 (3.45%)
    9 / 42 (21.43%)
    0 / 1 (0.00%)
         occurrences all number
    9
    9
    24
    1
    17
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 96 (0.00%)
    4 / 91 (4.40%)
    1 / 73 (1.37%)
    1 / 29 (3.45%)
    4 / 42 (9.52%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    1
    1
    5
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    3 / 96 (3.13%)
    1 / 91 (1.10%)
    5 / 73 (6.85%)
    0 / 29 (0.00%)
    1 / 42 (2.38%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    8
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2008
    • Inclusion of subjects with myelodysplastic syndromes (MDS) (low and intermediate-1-Risk (INT-1) risk as per International Prognostic Scoring System (IPSS) for MDS) with myocardial iron • Patient-reported outcomes/quality of life (QoL) assessments were removed • Safety monitoring of ocular and audiometry tests was clarified • Protocol deviations were no longer permissible • Introduction of deferasirox PK profile assessments • Extension of the screening period to 23 days and the washout period to 5 days • Clarification on the statistical analysis sections and analysis and reporting of CMR images • Safety section was updated with newly available information on deferasirox
    29 Oct 2008
    • Inclusion of subjects with severe myocardial siderosis (MRI T2* <10 ms) with additional CMR assessments. A T2* of 6 ms was specified as the lower cut-off; therefore, the trial was open to subjects with a myocardial T2* ≥ 6 to 20 ms • Clarification of the DFO dosing and regimen in order to ensure adequate dosing was in line with current guidelines for subjects with myocardial siderosis • Added that subjects will have an option to switch treatment to either deferasirox or DFO in the extension phase, if judged to be of therapeutic benefit by the investigator • Update of safety monitoring sections
    15 May 2009
    • Amendment of the exclusion criteria and concomitant medication sections in order to ensure consistency with the Exjade and Desferal labels. • Frequency of audiometry and height assessments increased • Pumps equivalent to “Microject Crono” allowed for use in the study • Dose administration section was revised due to findings of increased deferasirox concentrations in serum when taken with food • Increased urine protein from the notable laboratory abnormalities was replaced by increased urine protein/creatinine ratio • Dose modifications in case of low serum ferritin values were applied to both treatment groups to avoid any bias between these groups
    17 Mar 2010
    • Update of safety profile and monitoring sections • Inclusion/exclusion criteria modification in order to include more subjects with iron overload requiring chelation therapy in the study • Relaxing of re-screening criteria that allows subjects to be re-screened after 3 months when T2* values are above or below eligibility criteria or LVEF is below eligibility and after 1 month when alanine aminotransferase, serum creatinine, or urine protein/urine creatinine ratio is above the eligibility criterion • The screening period was extended to 35 days due to the inability of some subjects to complete the screening assessment period • New specification stating that visits were to be scheduled as closely as possible to the original planned date and that the planned date should always relate to the baseline • Addition of confirmatory assessment after 1 month in case LVEF falls below 50% or myocardial T2* decreases by ≥ 33% (withdrawal criteria) • MRI, ocular and audiometry assessments scheduled not later than within 30 days after the relevant visit date • Clarified and aligned with ICH-E9 guidelines the definition in the analysis section of the core protocol and added definitions on analysis sets and analysis to be conducted in the extension phase • To adapt the dosing scheme in for patients whose weight was greater than 70 kg • Additional ocular assessments in the extension phase at month 18 were added

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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