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    Clinical Trial Results:
    A multi-center, open-label, non-comparative, phase II trial on efficacy and safety of ICL670 given for 1 year with dose adjustments based on serum ferritin in patients with chronic anemia and transfusional hemosiderosis A one-year extension to a multi-center, open-label, non-comparative, phase II trial on efficacy and safety of ICL670 given for 1 year with dose adjustments based on serum ferritin in patients with chronic anemia and transfusional hemosiderosis

    Summary
    EudraCT number
    		 2006-003337-32
    Trial protocol
    		 ES  
    Global end of trial date
    02 Feb 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CICL670A2204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00631163
    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
    02 Feb 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of deferasirox, based on liver ion concentration (LIC) decrease over one year in paediatric and adult subjects with chronic anemias and transfusional hemosiderosis other than β-thalassemia or sickle cell disease.
    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
    22 Oct 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Japan: 53
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Turkey: 22
    Worldwide total number of subjects
    102
    EEA total number of subjects
    24
    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)
    16
    Adolescents (12-17 years)
    8
    Adults (18-64 years)
    41
    From 65 to 84 years
    36
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 31 centres in 5 countries.

    Pre-assignment
    Screening details
    		 A total of 144 subjects were screened, of which only 102 subjects enrolled in the study. Remaining 42 subjects were considered as screen failures.

    Period 1
    Period 1 title
    Core study
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study, hence no blinding was implemented.

    Arms
    Arm title
    		 Deferasirox (Core Study)
    Arm description
    		 The recommended initial daily dose of deferasirox was 20 mg/kg based on the patient’s body weight. An initial daily dose of 30 mg/kg was considered for patients receiving > 14 mL/kg/month of blood transfusions (defined as approximately more than 4 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was reduction of iron overload. Alternatively, an initial daily dose of 10 mg/kg was considered for patients receiving < 7 mL/kg/month of blood transfusions (defined as approximately less than 2 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was maintenance of iron level.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Deferasirox
    Investigational medicinal product code
    ICL670
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Deferasirox 20 mg/kg was administered once daily. The dose of deferasirox was adjusted to either 10 mg/kg or 30 mg/kg based on the volumes of blood transfusions being administered in a month.

    Number of subjects in period 1
    		Deferasirox (Core Study)
    Started
    102
    Completed
    68
    Not completed
    34
         Consent withdrawn by subject
    8
         Adverse event, non-fatal
    12
         Death
    6
         Subject's condition no longer required study drug
    1
         Administrative problems
    6
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Extension Study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was open-label, hence no blinding was implemented.

    Arms
    Arm title
    		 Deferasirox (Extension study)
    Arm description
    		 The recommended initial daily dose of deferasirox was 20 mg/kg based on the patient’s body weight. An initial daily dose of 30 mg/kg was considered for patients receiving > 14 mL/kg/month of blood transfusions (defined as approximately more than 4 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was reduction of iron overload. Alternatively, an initial daily dose of 10 mg/kg was considered for patients receiving < 7 mL/kg/month of blood transfusions (defined as approximately less than 2 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was maintenance of iron level.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Deferasirox
    Investigational medicinal product code
    ICL670
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Deferasirox 20 mg/kg was administered once daily. The dose of deferasirox was adjusted to either 10 mg/kg or 30 mg/kg based on the volumes of blood transfusions being administered in a month.

    Number of subjects in period 2 [1]
    		Deferasirox (Extension study)
    Started
    57
    Completed
    52
    Not completed
    5
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    1
         Abnormal laboratory values
    1
         Protocol deviation
    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 68 subjects who completed the preceding period, only 57 subjects opted to enroll in extension study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Deferasirox (Core Study)
    Reporting group description
    		 The recommended initial daily dose of deferasirox was 20 mg/kg based on the patient’s body weight. An initial daily dose of 30 mg/kg was considered for patients receiving > 14 mL/kg/month of blood transfusions (defined as approximately more than 4 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was reduction of iron overload. Alternatively, an initial daily dose of 10 mg/kg was considered for patients receiving < 7 mL/kg/month of blood transfusions (defined as approximately less than 2 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was maintenance of iron level.

    Reporting group values
    		 Deferasirox (Core Study) Total
    Number of subjects
    		 102 102
    Age categorical
    Units: Subjects
        2 years to < 6years
    		 11 11
        6 years to <12 years
    		 5 5
        12 years to <18 years
    		 8 8
        18 years to < 65 years
    		 41 41
        >= 65 years
    		 37 37
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.8 ( 25.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 49 49
        Male
    		 53 53

    End points

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    End points reporting groups
    Reporting group title
    Deferasirox (Core Study)
    Reporting group description
    		 The recommended initial daily dose of deferasirox was 20 mg/kg based on the patient’s body weight. An initial daily dose of 30 mg/kg was considered for patients receiving > 14 mL/kg/month of blood transfusions (defined as approximately more than 4 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was reduction of iron overload. Alternatively, an initial daily dose of 10 mg/kg was considered for patients receiving < 7 mL/kg/month of blood transfusions (defined as approximately less than 2 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was maintenance of iron level.
    Reporting group title
    Deferasirox (Extension study)
    Reporting group description
    		 The recommended initial daily dose of deferasirox was 20 mg/kg based on the patient’s body weight. An initial daily dose of 30 mg/kg was considered for patients receiving > 14 mL/kg/month of blood transfusions (defined as approximately more than 4 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was reduction of iron overload. Alternatively, an initial daily dose of 10 mg/kg was considered for patients receiving < 7 mL/kg/month of blood transfusions (defined as approximately less than 2 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was maintenance of iron level.

    Subject analysis set title
    All randomised subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The recommended initial daily dose of deferasirox was 20 mg/kg based on the patient’s body weight. An initial daily dose of 30 mg/kg was considered for patients receiving > 14 mL/kg/month of blood transfusions (defined as approximately more than 4 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was reduction of iron overload. Alternatively, an initial daily dose of 10 mg/kg was considered for patients receiving < 7 mL/kg/month of blood transfusions (defined as approximately less than 2 units (200 mL/unit) of packed red blood cells/month for adults) and the objective was maintenance of iron level.

    Subject analysis set title
    Japanese subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who were enrolled in Japan and received deferasirox as per the study protocol.

    Primary: Absolute change from baseline in liver iron concentration (LIC) to Year 1

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    End point title
    		 Absolute change from baseline in liver iron concentration (LIC) to Year 1 [1]
    End point description
    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 < 7, ≥ 7 to < 15, and ≥ 15 milligram of iron/tissue dry weight (mg Fe/g dw). A negative change from baseline favored study treatment in reducing LIC. The analysis was performed in per-protocol population in core study (PP1 Set), comprising of all enrolled subjects who had LIC assessments at baseline and Year 1.
    End point type
    Primary
    End point timeframe
    Baseline, Year 1 (End of core study)
    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 summary results available, no comparative statistics available
    End point values
    		 Deferasirox (Core Study)
    Number of subjects analysed
    50
    Units: mg Fe/g dw
        arithmetic mean (standard deviation)
    -10.9 ( 11.86 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in liver iron concentration (LIC) to end of Year 2

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    End point title
    		 Absolute change from baseline in liver iron concentration (LIC) to end of Year 2
    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 < 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 per-protocol population in core study (PP2 Set), comprising of all enrolled subjects who had LIC assessments at baseline and at end of the extension phase.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Year 2 (End of extension study)
    End point values
    		 Deferasirox (Extension study)
    Number of subjects analysed
    41
    Units: mg Fe/g dw
        arithmetic mean (standard deviation)
    -13.5 ( 14.1 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in LIC in Japanese subgroup

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    End point title
    		 Absolute change from baseline in LIC in Japanese subgroup
    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 was < 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 PP1 set in Japanese subgroup defined as all subjects who were enrolled in Japan for core study (Year 1) and PP2 set in Japanese subgroup for extension study (Year 2). Here, 'n' signifies the subjects assessed for LIC in Japanese subgroup for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Year 1 (End of core study), End of Year 2 (End of extension study)
    End point values
    		 Japanese subjects
    Number of subjects analysed
    31
    Units: mg Fe/g dw
    arithmetic mean (standard deviation)
        Year 1 (n= 31)
    -13.9 ( 10.21 )
        Year 2 (n= 26)
    -18.4 ( 12.48 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in serum ferritin levels to Year 2

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    End point title
    		 Absolute change from baseline in serum ferritin levels to Year 2
    End point description
    Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content. The analysis was performed in PP2 Set population and Japanese subgroup. Here, "Number of subjects analysed" signifies the subjects assessed for serum ferritin during the study for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline up to Year 2 (End of extension study)
    End point values
    		 All randomised subjects Japanese subjects
    Number of subjects analysed
    98
    51
    Units: nanogram(s)/millilitre
        arithmetic mean (standard deviation)
    -677.9 ( 4462.11 )
    -892.8 ( 5724.89 )
    No statistical analyses for this end point

    Secondary: Absolute serum ferritin levels over 2 years

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    End point title
    		 Absolute serum ferritin levels over 2 years
    End point description
    Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content. The analysis was performed in PP1 set population for core study (Year 1) and PP2 set population for extension study (Year 2) and Japanese subgroup. Here, "Number of subjects analysed" signifies the subjects assessed for serum ferritin during the study for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1 (End of core study), Year 2 (End of extension study)
    End point values
    		 All randomised subjects Japanese subjects
    Number of subjects analysed
    50
    31
    Units: nanogram(s)/millilitre
    arithmetic mean (standard deviation)
        Year 1
    2653.3 ( 5281.3 )
    2903.5 ( 3376 )
        Year 2
    2092.4 ( 2287.11 )
    2114.8 ( 2391.31 )
    No statistical analyses for this end point

    Secondary: Total body iron elimination rate (TBIE), Iron intake, Iron excretion/iron intake and chelation efficiency after 2 years

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    End point title
    		 Total body iron elimination rate (TBIE), Iron intake, Iron excretion/iron intake and chelation efficiency after 2 years
    End point description
    Total body iron excretion (TBIE)was used to investigate the chelation efficacy of deferasirox therapy. TBIE rate was estimated based on the iron influx as determined by the amount of red cells transfused and the change in total body iron (TBI) stores. The analysis was performed in PP2 set population and Japanese subgroup. Here, "Number of subjects analysed" signifies the subjects assessed for TBIE in the study arm. Total body iron elimination rate (TBIE), Iron intake, Iron excretion/iron intake and chelation efficiency
    End point type
    Secondary
    End point timeframe
    Baseline, Year 2 (End of extension study)
    End point values
    		 Deferasirox (Extension study) Japanese subjects
    Number of subjects analysed
    41
    26
    Units: ratio
    arithmetic mean (standard deviation)
        TBIE
    0.46 ( 0.252 )
    0.54 ( 0.215 )
        Iron intake
    0.27 ( 0.15 )
    0.27 ( 0.16 )
        Iron excretion/iron intake
    2 ( 1.368 )
    2.44 ( 1.417 )
        Chelation efficiency
    0.4 ( 0.221 )
    0.5 ( 0.177 )
    No statistical analyses for this end point

    Secondary: Correlation of LIC and serum ferritin at core and extension study

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    End point title
    		 Correlation of LIC and serum ferritin at core and extension study
    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 was < 7, ≥ 7 to < 15, and ≥ 15 mg Fe/g dw. Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content. The correlation between absolute change in LIC and absolute change in serum ferritin was determined. The analysis was performed in PP1 set for core study (Year 1) and PP2 set for extension study (Year 2). Here, "Number of subjects analysed" signifies the subjects assessed for LIC and serum ferritin during the study for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1 (End of core study), Year 2 (End of extension study)
    End point values
    		 Deferasirox (Core Study) Deferasirox (Extension study)
    Number of subjects analysed
    50
    40
    Units: Correlation coefficient
        number (not applicable)
    0.291
    0.325
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs), adverse event of special interest (AESI), discontinuation and interruption

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    End point title
    		 Number of subjects with adverse events (AEs), serious adverse events (SAEs), adverse event of special interest (AESI), discontinuation and interruption
    End point description
    Adverse events (AEs) were defined as any unfavourable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require hospitalisation, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. Death was defined as a fatal event leading to permanent cessation of all vital functions of the body. The analysis was performed in the safety set (SAF) population, defined as subjects who received at least one dose of study drug, which was defined as at least one administration record with a valid date and an actual total daily dose administrated above zero, and Japanese sub-group.
    End point type
    Secondary
    End point timeframe
    Baseline up to Year 2 (End of extension study)
    End point values
    		 All randomised subjects Japanese subjects
    Number of subjects analysed
    102
    53
    Units: Subjects
        AEs
    97
    53
        SAEs
    46
    25
        Death
    5
    4
        Mild AEs
    17
    5
        Moderate AEs
    39
    25
        Severe AEs
    41
    23
        AEs suspected to study drug
    65
    43
        SAEs suspected to study drug
    10
    6
        AEs leading to discontinuation of study drug
    14
    7
        AEs leading to dose adjustment/interruption
    67
    42
        AESI
    62
    39
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically significant ophthalmological abnormalities

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    End point title
    		 Number of subjects with clinically significant ophthalmological abnormalities
    End point description
    Clinically significant changes in left eye and right eye were assessed by the investigator based on methods like visual acuity, slit lamp examination, tonometry and fundus oculi. The analysis was performed in the SAF population and Japanese subgroup. These patients comprise 2 year completer groups
    End point type
    Secondary
    End point timeframe
    2 years (End of extension study)
    End point values
    		 All randomised subjects Japanese subjects
    Number of subjects analysed
    50 [2]
    28 [3]
    Units: Subjects
        Normal
    25
    12
        Abnormal Clin Insignificant
    15
    12
        Abnormal Clin Significant
    10
    4
        Not Available
    0
    0
        Total
    50
    28
    Notes
    [2] - number of patients at end of trial- completer group
    [3] - Number of japanese patients at end of trial with occular measurements- 2 year completers
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment until LSLV.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    myelodysplastic syndrome
    Reporting group description
    		 myelodysplastic syndrome

    Reporting group title
    Other
    Reporting group description
    		 very rare diseases (e.g. Diamond Blackfan anemia, myelofibrosis, specific enzyme deficiency).

    Reporting group title
    aplastic anemia
    Reporting group description
    		 aplastic anemia,

    Serious adverse events
    		 myelodysplastic syndrome Other aplastic anemia
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 42 (52.38%)
    10 / 31 (32.26%)
    14 / 29 (48.28%)
         number of deaths (all causes)
    1
    1
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ABDOMINAL NEOPLASM
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    BLADDER NEOPLASM
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYELOFIBROSIS
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    RECTAL CANCER
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST DISCOMFORT
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    DISUSE SYNDROME
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    FATIGUE
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    GENERALISED OEDEMA
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    MALAISE
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    0 / 29 (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
    PYREXIA
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ADENOIDAL HYPERTROPHY
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    HYPOXIA
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    Psychiatric disorders
    NEUROSIS
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    BODY HEIGHT BELOW NORMAL
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    TOOTH FRACTURE
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    TRAUMATIC HAEMORRHAGE
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    TRAUMATIC INTRACRANIAL HAEMORRHAGE
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    0 / 29 (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
    ATRIAL FLUTTER
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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 FAILURE
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    PERICARDITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    Nervous system disorders
    CEREBELLAR HAEMORRHAGE
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL INFARCTION
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    DIZZINESS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    APLASTIC ANAEMIA
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DISSEMINATED INTRAVASCULAR COAGULATION
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    CATARACT
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    RETINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    Gastrointestinal disorders
    ASCITES
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    DIARRHOEA
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    ENTEROCOLITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL ULCER
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    PERIODONTAL DISEASE
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    PERIODONTITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    RADICULAR CYST
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    VOMITING
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    Skin and subcutaneous tissue disorders
    HAEMORRHAGE SUBCUTANEOUS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    PANNICULITIS
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    RASH ERYTHEMATOUS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    SKIN ULCER
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    URTICARIA
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    FANCONI SYNDROME ACQUIRED
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    Endocrine disorders
    DELAYED PUBERTY
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    Musculoskeletal and connective tissue disorders
    BONE PAIN
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    BONE SWELLING
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    Infections and infestations
    BACTERIAL INFECTION
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    BRONCHITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    BRONCHOPNEUMONIA
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    FUNGAEMIA
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    FUNGAL OESOPHAGITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    GASTRITIS VIRAL
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    GASTROENTERITIS
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    INFLUENZA
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORAL HERPES
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    PARONYCHIA
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERTUSSIS
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    PHARYNGITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    PNEUMONIA
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    0 / 29 (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
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    ZYGOMYCOSIS
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    HYPERCALCAEMIA
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    0 / 29 (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
    HYPOGLYCAEMIA
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    0 / 29 (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
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (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
    		 myelodysplastic syndrome Other aplastic anemia
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 42 (92.86%)
    25 / 31 (80.65%)
    25 / 29 (86.21%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    4
    0
    1
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    3
    0
    3
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    3
    1
    2
    CHEST PAIN
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    1
    0
    4
    FACE OEDEMA
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    0
    3
    FATIGUE
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 31 (9.68%)
    1 / 29 (3.45%)
         occurrences all number
    3
    3
    1
    MALAISE
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 31 (6.45%)
    4 / 29 (13.79%)
         occurrences all number
    2
    2
    6
    OEDEMA PERIPHERAL
         subjects affected / exposed
    14 / 42 (33.33%)
    1 / 31 (3.23%)
    7 / 29 (24.14%)
         occurrences all number
    19
    2
    15
    PYREXIA
         subjects affected / exposed
    11 / 42 (26.19%)
    6 / 31 (19.35%)
    9 / 29 (31.03%)
         occurrences all number
    22
    11
    16
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 31 (16.13%)
    2 / 29 (6.90%)
         occurrences all number
    2
    5
    3
    DYSPNOEA
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    3
    2
    1
    EPISTAXIS
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 31 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    2
    NASAL CONGESTION
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    0
    3
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 31 (3.23%)
    3 / 29 (10.34%)
         occurrences all number
    1
    1
    3
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    2
    RHINITIS ALLERGIC
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 31 (6.45%)
    1 / 29 (3.45%)
         occurrences all number
    0
    3
    1
    Psychiatric disorders
    DELIRIUM
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    0
    INSOMNIA
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    8
    1
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 31 (9.68%)
    1 / 29 (3.45%)
         occurrences all number
    4
    3
    4
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    2
    1
    3
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 31 (6.45%)
    3 / 29 (10.34%)
         occurrences all number
    1
    2
    4
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    16 / 42 (38.10%)
    2 / 31 (6.45%)
    8 / 29 (27.59%)
         occurrences all number
    29
    4
    19
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 31 (0.00%)
    5 / 29 (17.24%)
         occurrences all number
    7
    0
    9
    PROTEIN URINE PRESENT
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 31 (16.13%)
    1 / 29 (3.45%)
         occurrences all number
    3
    10
    1
    WEIGHT DECREASED
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 31 (6.45%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    2
    Injury, poisoning and procedural complications
    ALLERGIC TRANSFUSION REACTION
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    4
    1
    1
    CONTUSION
         subjects affected / exposed
    6 / 42 (14.29%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    6
    0
    5
    FALL
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    2
    0
    3
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    0
    2
    TOOTH INJURY
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    2
    TRANSFUSION REACTION
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    5
    1
    3
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    4
    0
    2
    CARDIAC FAILURE
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    4
    1
    2
    TACHYCARDIA
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    3
    1
    3
    Nervous system disorders
    DYSGEUSIA
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    0
    2
    HEADACHE
         subjects affected / exposed
    8 / 42 (19.05%)
    3 / 31 (9.68%)
    4 / 29 (13.79%)
         occurrences all number
    9
    5
    5
    SOMNOLENCE
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    1
    1
    2
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    5 / 42 (11.90%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    5
    1
    1
    APLASTIC ANAEMIA
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    2
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    0
    1
    2
    THROMBOCYTOPENIA
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    4
    0
    2
    Eye disorders
    CATARACT
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    4
    0
    2
    CONJUNCTIVAL HAEMORRHAGE
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    4
    0
    1
    EYE PAIN
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    0
    3
    RETINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 31 (9.68%)
    3 / 29 (10.34%)
         occurrences all number
    2
    3
    5
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    3 / 29 (10.34%)
         occurrences all number
    0
    3
    6
    ABDOMINAL DISTENSION
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    0
    1
    ABDOMINAL PAIN
         subjects affected / exposed
    7 / 42 (16.67%)
    2 / 31 (6.45%)
    4 / 29 (13.79%)
         occurrences all number
    8
    2
    4
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 31 (3.23%)
    3 / 29 (10.34%)
         occurrences all number
    4
    1
    3
    APHTHOUS STOMATITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    2
    CONSTIPATION
         subjects affected / exposed
    13 / 42 (30.95%)
    3 / 31 (9.68%)
    5 / 29 (17.24%)
         occurrences all number
    15
    3
    6
    DENTAL CARIES
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    3
    0
    2
    DIARRHOEA
         subjects affected / exposed
    10 / 42 (23.81%)
    5 / 31 (16.13%)
    7 / 29 (24.14%)
         occurrences all number
    13
    7
    8
    GASTRITIS
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    0
    2
    HAEMORRHOIDS
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    3
    0
    3
    NAUSEA
         subjects affected / exposed
    9 / 42 (21.43%)
    2 / 31 (6.45%)
    6 / 29 (20.69%)
         occurrences all number
    10
    2
    7
    STOMATITIS
         subjects affected / exposed
    8 / 42 (19.05%)
    0 / 31 (0.00%)
    7 / 29 (24.14%)
         occurrences all number
    8
    0
    10
    VOMITING
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    5
    0
    4
    Hepatobiliary disorders
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    3
    0
    2
    Skin and subcutaneous tissue disorders
    DERMATITIS ALLERGIC
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    0
    3
    0
    DRY SKIN
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 31 (12.90%)
    3 / 29 (10.34%)
         occurrences all number
    1
    4
    3
    MADAROSIS
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    0
    3
    0
    PETECHIAE
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    4
    1
    0
    PRURITUS
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 31 (3.23%)
    4 / 29 (13.79%)
         occurrences all number
    2
    2
    4
    RASH
         subjects affected / exposed
    11 / 42 (26.19%)
    1 / 31 (3.23%)
    3 / 29 (10.34%)
         occurrences all number
    17
    1
    3
    SKIN ULCER
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    2
    3
    0
    Renal and urinary disorders
    PROTEINURIA
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    4
    1
    1
    RENAL FAILURE
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 31 (6.45%)
    3 / 29 (10.34%)
         occurrences all number
    6
    2
    7
    RENAL IMPAIRMENT
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 31 (6.45%)
    6 / 29 (20.69%)
         occurrences all number
    7
    4
    7
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    0
    1
    BACK PAIN
         subjects affected / exposed
    7 / 42 (16.67%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    7
    1
    3
    MUSCLE SPASMS
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 31 (3.23%)
    3 / 29 (10.34%)
         occurrences all number
    3
    1
    3
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 31 (9.68%)
    1 / 29 (3.45%)
         occurrences all number
    3
    3
    1
    MYALGIA
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 31 (6.45%)
    1 / 29 (3.45%)
         occurrences all number
    4
    2
    1
    PAIN IN EXTREMITY
         subjects affected / exposed
    5 / 42 (11.90%)
    3 / 31 (9.68%)
    2 / 29 (6.90%)
         occurrences all number
    5
    4
    2
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 31 (12.90%)
    0 / 29 (0.00%)
         occurrences all number
    2
    6
    0
    CYSTITIS
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    9
    0
    4
    EAR INFECTION
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    0
    2
    0
    FURUNCLE
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    3
    HERPES SIMPLEX
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    0
    HERPES ZOSTER
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    4
    0
    0
    INFLUENZA
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 31 (6.45%)
    3 / 29 (10.34%)
         occurrences all number
    1
    2
    3
    NASOPHARYNGITIS
         subjects affected / exposed
    14 / 42 (33.33%)
    6 / 31 (19.35%)
    10 / 29 (34.48%)
         occurrences all number
    36
    18
    21
    ORAL CANDIDIASIS
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    0
    OTITIS MEDIA
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    0
    3
    2
    OTITIS MEDIA CHRONIC
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 31 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    2
    PHARYNGITIS
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 31 (6.45%)
    1 / 29 (3.45%)
         occurrences all number
    3
    5
    1
    TONSILLITIS
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 31 (9.68%)
    0 / 29 (0.00%)
         occurrences all number
    2
    9
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 42 (2.38%)
    9 / 31 (29.03%)
    2 / 29 (6.90%)
         occurrences all number
    3
    29
    3
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 31 (9.68%)
    0 / 29 (0.00%)
         occurrences all number
    6
    5
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    7 / 42 (16.67%)
    1 / 31 (3.23%)
    4 / 29 (13.79%)
         occurrences all number
    9
    1
    7
    DEHYDRATION
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 31 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    6
    0
    4
    DIABETES MELLITUS
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 31 (3.23%)
    2 / 29 (6.90%)
         occurrences all number
    4
    1
    2
    HYPOGLYCAEMIA
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 31 (3.23%)
    4 / 29 (13.79%)
         occurrences all number
    6
    1
    5
    HYPOKALAEMIA
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    4
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2006
    • Added a recommendation to refer patients whose serum creatinine remained elevated despite dose reduction and interruption, and in whom there was also a persistent abnormality of another marker of renal function (e.g. proteinuria, Fanconi’s syndrome), to a renal specialist for further specialized investigations • Updated the language for a potential dose adjustment, which was updated as a standard for all Exjade clinical protocols • Amended the exclusion criterion for patients with a baseline serum creatinine level that was above the ULN • Removed the language regarding the availability of commercial Exjade that triggered a withdrawal of the patient from the study • Changed the collection of data with an eCRF to collection on a paper CRF.
    02 May 2007
    • Modified the study design and scope to investigate the safety and efficacy of deferasirox in patients with transfusion-dependent anemias other than ß-thalassemia or sickle cell disease, especially in Japanese patients; this included the removal of the baseline LIC classification (i.e. < 7 mg Fe/g dw vs. ≥ 7 mg Fe/g dw) • Revised the primary endpoint: absolute change in LIC from baseline to end of Year 1 • Revised the endpoint, change in serum ferritin from baseline to end of study, to a secondary efficacy assessment • Excluded patients with either ß-thalassemia or sickle cell disease • Increased the serum ferritin inclusion criterion to more than 1000 ng/mL • Reduced the sample size estimate to 114 enrolled patients, which included 50 Japanese patients enrolled in Japan, using nQuery Advisor Version 5.0 • Extended the ophthalmologic assessments for an additional year (i.e. Year 2) in at least 60 patients • Updated the informed consent form
    29 Aug 2007
    • Revised the protocol to include reference to the yearly audiometric tests: this was part of the revised informed consent form issued with Amendment 2 • Modified the collection of ECG assessments at baseline only and can be repeated in the event of a cardiac adverse event • Clarified the assessments for the routine urinalysis and microscopic analysis only in case of a positive dipstick
    29 Apr 2008
    • Revised the protocol introduction to include new safety information on deferasirox that has emerged since the original protocol was issued • Increased clarity on the definition of the Per-protocol population • Modified the criteria for the analyses on serum ferritin changes during the study • Introduced greater protocol adherence by avoidance of protocol deviations • Updated the informed consent form
    05 Aug 2008
    • Extended the duration of the study to include Year 2 to collect long-term data for safety and efficacy • Continued assessments for hematology, biochemistry, and urinalysis on a monthly basis • Repeated physical examination every 6 months • Performed measurements of LIC, audiometry, and prothrombin time after one year of treatment again • Assessed growth velocity and sexual development in pediatric patients • Clarified when Year 2 started in relation to the end of Year 1 dosing • Defined that baseline values during the core phase were used as a reference for a potential dose adjustment

    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.
    None reported
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