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    Clinical Trial Results:
    A randomized, open-label, multicenter, two arm, phase II study to investigate the benefits of an improved deferasirox formulation (film-coated tablet)

    Summary
    EudraCT number
    		 2013-004167-32
    Trial protocol
    		 AT   ES   IT   GB   FR   GR  
    Global end of trial date
    24 Feb 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Aug 2017
    First version publication date
    09 Sep 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    The time frame for the primary end point was updated to 28 weeks.

    Trial information

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    Trial identification
    Sponsor protocol code
    CICL670F2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02125877
    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 613421111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613421111,
    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
    24 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the overall safety of deferasirox FCT and deferasirox DT formulations in patients with transfusion-dependent thalassemia or myelodysplastic syndrome at very low, low or intermediate (int) risk.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jul 2014
    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
    Argentina: 2
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Italy: 52
    Country: Number of subjects enrolled
    Lebanon: 20
    Country: Number of subjects enrolled
    Malaysia: 10
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Saudi Arabia: 9
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    United Arab Emirates: 13
    Worldwide total number of subjects
    173
    EEA total number of subjects
    102
    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)
    2
    Adolescents (12-17 years)
    19
    Adults (18-64 years)
    126
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Deferasirox dispersible tablet (DFX-DT)
    Arm description
    		 Iron chelation naïve participants received DFX-DT 20 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 5 to 10 mg/kg/day, with a maximum dose of 40 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Deferasirox (DFX-DT)
    Investigational medicinal product code
    ICL670
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Iron chelation naïve participants received DFX-DT 20 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 5 to 10 mg/kg/day, with a maximum dose of 40 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose.

    Arm title
    		 Deferasirox film-coated tablet (DFX-FCT)
    Arm description
    		 Participants received DFX-FCT 14 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 3.5 to 7 mg/kg/day, with a maximum dose of 28 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Deferasirox (DFX-FCT)
    Investigational medicinal product code
    ICL670
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received DFX-FCT 14 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 3.5 to 7 mg/kg/day, with a maximum dose of 28 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose

    Number of subjects in period 1
    		Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Started
    86
    87
    Pharmacokinetic analysis set
    83
    83
    Pharmacokinetic subset A
    16 [1]
    15 [2]
    Safety set
    86
    87
    Completed
    73
    77
    Not completed
    13
    10
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    2
    1
         Physician decision
    1
    -
         Adverse event, non-fatal
    6
    4
         Protocol deviation
    4
    1
         Administrative problems
    -
    1
         Participant/guardian decision
    -
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number is correct.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number is correct.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Deferasirox dispersible tablet (DFX-DT)
    Reporting group description
    		 Iron chelation naïve participants received DFX-DT 20 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 5 to 10 mg/kg/day, with a maximum dose of 40 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose.

    Reporting group title
    Deferasirox film-coated tablet (DFX-FCT)
    Reporting group description
    		 Participants received DFX-FCT 14 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 3.5 to 7 mg/kg/day, with a maximum dose of 28 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose

    Reporting group values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT) Total
    Number of subjects
    		 86 87 173
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 2 0 2
        Adolescents (12-17 years)
    		 8 11 19
        Adults (18-64 years)
    		 64 62 126
        From 65-84 years
    		 12 14 26
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 35.1 ( 18.6 ) 34.6 ( 19.97 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 47 41 88
        Male
    		 39 46 85

    End points

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    End points reporting groups
    Reporting group title
    Deferasirox dispersible tablet (DFX-DT)
    Reporting group description
    		 Iron chelation naïve participants received DFX-DT 20 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 5 to 10 mg/kg/day, with a maximum dose of 40 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose.

    Reporting group title
    Deferasirox film-coated tablet (DFX-FCT)
    Reporting group description
    		 Participants received DFX-FCT 14 mg/kg/day once daily orally from weeks 1 - 4. After week 4, the dose could be adjusted by +/- 3.5 to 7 mg/kg/day, with a maximum dose of 28 mg/kg/day. Iron chelation pre-treated participants were supposed to start on a dose that was equivalent to their pre-washout dose

    Primary: Overall safety as measured by adverse events

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    End point title
    		 Overall safety as measured by adverse events [1]
    End point description
    The percentage of participants with adverse events, serious adverse events and deaths was assessed.
    End point type
    Primary
    End point timeframe
    28 weeks
    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: Statistical analysis does not apply to this end point.
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: Percentage of participants
    number (not applicable)
        Adverse events
    89.5
    89.7
        SAEs
    15.1
    18.4
        Deaths
    0
    1.1
    No statistical analyses for this end point

    Primary: Overall safety as measured by changes in laboratory values from baseline

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    End point title
    		 Overall safety as measured by changes in laboratory values from baseline [2]
    End point description
    The percentage of participants with post-baseline laboratory values meeting specified criteria for notable/extended range was assessed. The following laboratory parameters were measured: platelet count, absolute neutrophils, serum creatinine , creatinine clearance, urinary protein/urinary creatinine ratio, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Note that within data categories, creat = creatinine, cons = consecutive, ULN = upper limit of normal and urin = urinary.
    End point type
    Primary
    End point timeframe
    30 weeks
    Notes
    [2] - 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: Statistical analysis does not apply to this end point.
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: Percentage of participants
    number (not applicable)
        platelet count, notable range: <100 x 10^9/L
    9.3
    8
        platelet count, extended range: <50 x 10^9/L
    3.5
    5.7
        absolute neutrophils, notable range: <1.5 x 10^9/L
    8.1
    13.8
        absolute neutrophils, extended range: <0.5 x10^9/L
    4.7
    0
        serum creat, 2 cons >33% inc from BL and >ULN
    4.7
    3.4
        creat clearance, notable range: 2 cons <60 mL/min
    7
    2.3
        creat clearance, extended range: 2 cons <40 mL/min
    2.3
    2.3
        urin protein/urin creat ratio, 2 cons >1.0 mg/mg
    2.3
    0
        ALT, notable range: >5 x ULN and >2 x BL
    1.2
    1.1
        ALT, extended range: >10 x ULN and >2 x BL
    1.2
    0
        AST, notable range: >5 x ULN and >2 x BL
    0
    1.1
        AST, extended range: >10 x ULN and >2 x BL
    1.2
    0
    No statistical analyses for this end point

    Secondary: Frequency of selected gastro-intestinal (GI) adverse events

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    End point title
    		 Frequency of selected gastro-intestinal (GI) adverse events
    End point description
    The percentage of participants with any GI adverse event, diarrhea, constipation, nausea, vomiting, abdominal pain was assessed.
    End point type
    Secondary
    End point timeframe
    28 weeks
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: Percentage of participants
    number (not applicable)
        Any GI adverse event
    61.6
    58.6
        Abdominal pain
    26.7
    26.4
        Constipation
    15.1
    8
        Diarrhea
    34.9
    33.3
        Nausea
    26.7
    27.6
        Vomiting
    22.1
    17.2
    No statistical analyses for this end point

    Secondary: Mean domain scores of the modified Satisfaction with Iron Chelation Therapy (modified SICT)

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    End point title
    		 Mean domain scores of the modified Satisfaction with Iron Chelation Therapy (modified SICT)
    End point description
    The modified SICT consisted of 13 items that represent 3 domains: adherence, satisfaction and concerns. The adherence domain consisted of 7 items, 6 which were measured using a 5-point response scale and was calculated by summing the 6 items. The score range from 6 to 30 and higher scores indicated worse adherence. The satisfaction domain consisted of 3 items, 2 which were measured using a 5-point response scale and was calculated by summing the 2 items. The score range from 2 to 10 and higher scores indicated worse satisfaction. The concerns domain consisted of 3 items to address any concerns or worries with his/her medication. All 3 items were measured on a 5-point response scale and were calculated by summing the 3 items. The score range from 3 to 15 and higher scores indicated fewer concerns. For all three domains, the meaningful difference between two treatment arms was determined to be 1 point.
    End point type
    Secondary
    End point timeframe
    weeks 2, 3, 13 and 24 (end of treatment or within 7 days of last dose)
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: score on a scale
    arithmetic mean (standard deviation)
        week 2, adherence (n=70,70)
    10.3 ( 3.8 )
    7.6 ( 2.14 )
        week 2, satisfaction/preference (n=70,70)
    5.2 ( 2.24 )
    2.8 ( 1.37 )
        week 2, concerns (n=70,70)
    12.9 ( 2.94 )
    13.8 ( 2.02 )
        week 3, adherence (n=58,51)
    10.9 ( 4.09 )
    7.7 ( 2.06 )
        week 3, satisfaction/preference (n=58,51)
    5.4 ( 2.22 )
    2.6 ( 1.05 )
        week 3, concerns (n=58,51)
    12.4 ( 2.73 )
    14 ( 1.49 )
        week 13, adherence (n=59,64)
    11.2 ( 3.56 )
    7.8 ( 2.05 )
        week 13, satisfaction/preference (n=59,64)
    5.4 ( 2.14 )
    2.9 ( 1.54 )
        week 13, concerns (n=59,64)
    12.7 ( 2.5 )
    13.6 ( 1.87 )
        week 24, adherence (n=63,60)
    12.5 ( 5.32 )
    7.5 ( 2.41 )
        week 24, satisfaction/preference (n=63,60)
    5.8 ( 2.28 )
    2.9 ( 1.58 )
        week 24, concerns (n=63,60)
    11.8 ( 3.07 )
    13.7 ( 1.84 )
    No statistical analyses for this end point

    Secondary: Palatability questionnaire score

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    End point title
    		 Palatability questionnaire score
    End point description
    The palatability questionnaire consisted of 4 items. The first item measured the taste and aftertaste of the medication and were scored a on a 5-point response scale. The second item offered an additional response option of "no aftertaste". The last 2 items referred to whether the medication was taken, i.e. swallowed or vomited, and how the participant perceived the amount of medication to be taken. The palatability summary score was calculated using a scoring matrix from items 1, 3 and 4 scores and the score ranges from 0 - 11. Higher scores indicated the best palatability. A meaningful difference between two treatment arms was determined to be 1 point.
    End point type
    Secondary
    End point timeframe
    weeks 2, 3, 13 and 24 (end of treatment or within 7 days of last dose)
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: score on a scale
    arithmetic mean (standard deviation)
        week 2 (n=69,70)
    9 ( 3.01 )
    10.8 ( 0.5 )
        week 3 (n=57,51)
    8.8 ( 3.01 )
    10.8 ( 0.45 )
        week 13 (n=59,62)
    9.3 ( 2.84 )
    10.8 ( 1.16 )
        week 24 (n=63,60)
    8.8 ( 3.1 )
    10.9 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Weekly average of daily scores of the gastrointestinal (GI) symptom diary

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    End point title
    		 Weekly average of daily scores of the gastrointestinal (GI) symptom diary
    End point description
    The GI symptom diary consisted of 6 items, five which were scored using a 0 - 10 rating scale with item appropriate anchors to rate the symptom, for example, Pain in your belly: 0 = no pain and 10 = worst pain. The GI diary summary score was created using the 10 point response scale for the 5 items. The GI symptom daily diary had a minimum score of 0 and a maximum score of 50. The weekly average score for the 7 days was calculated for each individual item and the GI summary score was created from these weekly averages. Higher scores indicated worse symptoms. A meaningful difference between two treatment arms was determined to be 0.3 point.
    End point type
    Secondary
    End point timeframe
    weeks -1, 4, 8, 12, 16, 20, 24
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: score on a scale
    arithmetic mean (standard deviation)
        week -1 (n=69,65)
    1.4 ( 2.1 )
    1.9 ( 3.69 )
        week 4 (n=60,64)
    1.8 ( 3.49 )
    1.1 ( 2.15 )
        week 8 (n=59,51)
    1.4 ( 2.45 )
    1.1 ( 2.16 )
        week 12 (n=51,45)
    1.7 ( 3.16 )
    1 ( 1.78 )
        week 16 (n=48,41)
    1.9 ( 3.75 )
    0.9 ( 1.92 )
        week 20 (n40,39)
    1.5 ( 3.27 )
    0.9 ( 1.44 )
        week 24 (n32,26)
    1.5 ( 3.29 )
    1.2 ( 1.89 )
    No statistical analyses for this end point

    Secondary: Number of participants with weekly average compliance of medication consumption

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    End point title
    		 Number of participants with weekly average compliance of medication consumption
    End point description
    A compliance questionnaire assessed whether the medication was taken. Weekly average compliance was calculated when there were at least four non-missing daily responses.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: Participants
        week 1
    56
    53
        week 2
    64
    64
        week 3
    62
    56
        week 4
    58
    58
        week 5
    56
    58
        week 6
    62
    51
        week 7
    55
    48
        week 8
    56
    46
        week 9
    53
    45
        week 10
    52
    46
        week 11
    50
    42
        week 12
    50
    41
        week 13
    49
    47
        week 14
    51
    42
        week 15
    48
    42
        week 16
    48
    40
        week 17
    43
    39
        week 18
    43
    38
        week 19
    40
    37
        week 20
    40
    36
        week 21
    39
    36
        week 22
    38
    34
        week 23
    36
    33
        week 24
    30
    24
    No statistical analyses for this end point

    Secondary: Weekly dose violation rate

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    End point title
    		 Weekly dose violation rate
    End point description
    The dose violation is defined as a dose either missed completely or not taken in accordance with the timing instruction (no later than 12:00 pm. The rate was calculated as [number of dose violations/drug exposure (days)] x 100.
    End point type
    Secondary
    End point timeframe
    weeks 1, 4, 8, 12, 16, 20, 24
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    86
    87
    Units: (number of dose violations/days)*100
    arithmetic mean (standard deviation)
        week 1 (n=56,53)
    17.7 ( 31.04 )
    15.8 ( 29.42 )
        week 4 (n=58,58)
    15.8 ( 32.51 )
    6.7 ( 15.45 )
        week 8 (n=56,46)
    18 ( 35.38 )
    8.4 ( 22.17 )
        week 12 (n=50,41)
    15.7 ( 34.22 )
    10.7 ( 22.63 )
        week 16 (n=48,40)
    13.5 ( 31.08 )
    10 ( 24.5 )
        week 20 (n=40,36)
    22.6 ( 38.38 )
    11.3 ( 26.67 )
        week 24 (n=30,24)
    17.1 ( 34.26 )
    10.1 ( 25.47 )
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast)

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    End point title
    		 Area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast)
    End point description
    Blood samples were collected to assess AUClast.
    End point type
    Secondary
    End point timeframe
    week 1, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose; week 3, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    16
    15
    Units: umol/L*h
    arithmetic mean (standard deviation)
        week1 (n=14,15)
    1110 ( 495 )
    1040 ( 405 )
        week 3 (n=13,15)
    1590 ( 540 )
    2110 ( 987 )
    No statistical analyses for this end point

    Secondary: Observed maximum plasma concentration following drug administration (Cmax)

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    End point title
    		 Observed maximum plasma concentration following drug administration (Cmax)
    End point description
    Blood samples were collected to assess Cmax.
    End point type
    Secondary
    End point timeframe
    week 1, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose; week 3, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    16
    15
    Units: umol/L
    arithmetic mean (standard deviation)
        week 1 (n=14,15)
    74.6 ( 30.7 )
    79.3 ( 23.5 )
        week 3 (n=14,15)
    118 ( 82.3 )
    139 ( 57.2 )
    No statistical analyses for this end point

    Secondary: Time to reach the maximum plasma concentration after drug administration (Tmax)

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    End point title
    		 Time to reach the maximum plasma concentration after drug administration (Tmax)
    End point description
    Blood samples were collected to assess Tmax.
    End point type
    Secondary
    End point timeframe
    week 1, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose; week 3, day 1: pre-dose (0 hour) and 1, 2, 3, 4, 8 and 24 hours post dose
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    16
    15
    Units: hour
    median (full range (min-max))
        week 1 (n=14,15)
    3.57 (1.15 to 7.89)
    2 (1.15 to 15.6)
        week 3 (n=14,15)
    2.85 (1.4 to 8.39)
    2.02 (1.07 to 5.06)
    No statistical analyses for this end point

    Secondary: Dererasirox plasma concentration

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    End point title
    		 Dererasirox plasma concentration
    End point description
    Blood samples were collected to assess deferasirox concentration. Dose-adjusted calculations are presented: (concentration/actual dose)*20 for participants on DFX-DT and (concentration/actual dose)*14 for participants on DFX-FCT.
    End point type
    Secondary
    End point timeframe
    Week 3, day 1, pre-dose (0 hour (h)) and 2 h post-dose; week 13, day 1, pre-dose (0 hour (h)) and 2 h post-dose; and week 21, day 1, pre-dose (0 hour (h)) and 2 h post-dose
    End point values
    		 Deferasirox dispersible tablet (DFX-DT) Deferasirox film-coated tablet (DFX-FCT)
    Number of subjects analysed
    83
    83
    Units: umol/L
    arithmetic mean (standard deviation)
        week 3, pre-dose (n=63,70)
    39.6 ( 48.4 )
    27.3 ( 20.4 )
        week 3, 2 hours post-dose (n=67,76)
    80.8 ( 52.2 )
    95.5 ( 53 )
        week 13, pre-dose (n=69.56)
    37.1 ( 37.8 )
    31.3 ( 22.9 )
        week 13, 2 hours post-dose (n=74,59)
    78.7 ( 39.5 )
    92.5 ( 39.1 )
        week 21, pre-dose (n=54,59)
    46.6 ( 46.4 )
    43.1 ( 36.8 )
        week 21, 2 hours post-dose (n=59,64)
    89.8 ( 59.3 )
    105 ( 51.2 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    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
    18.1
    Reporting groups
    Reporting group title
    DFX DT
    Reporting group description
    		 DFX DT

    Reporting group title
    DFX FCT
    Reporting group description
    		 DFX FCT

    Serious adverse events
    		 DFX DT DFX FCT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 86 (15.12%)
    16 / 87 (18.39%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delayed haemolytic transfusion reaction
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemolysis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brucellosis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural pneumonia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DFX DT DFX FCT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 86 (80.23%)
    72 / 87 (82.76%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    7 / 86 (8.14%)
    8 / 87 (9.20%)
         occurrences all number
    7
    11
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    11 / 86 (12.79%)
    17 / 87 (19.54%)
         occurrences all number
    15
    23
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 86 (13.95%)
    5 / 87 (5.75%)
         occurrences all number
    30
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 86 (9.30%)
    4 / 87 (4.60%)
         occurrences all number
    8
    4
    Fatigue
         subjects affected / exposed
    7 / 86 (8.14%)
    5 / 87 (5.75%)
         occurrences all number
    7
    5
    Pyrexia
         subjects affected / exposed
    7 / 86 (8.14%)
    7 / 87 (8.05%)
         occurrences all number
    8
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    23 / 86 (26.74%)
    23 / 87 (26.44%)
         occurrences all number
    33
    33
    Constipation
         subjects affected / exposed
    13 / 86 (15.12%)
    7 / 87 (8.05%)
         occurrences all number
    19
    10
    Abdominal pain upper
         subjects affected / exposed
    6 / 86 (6.98%)
    10 / 87 (11.49%)
         occurrences all number
    7
    11
    Diarrhoea
         subjects affected / exposed
    30 / 86 (34.88%)
    27 / 87 (31.03%)
         occurrences all number
    62
    55
    Dyspepsia
         subjects affected / exposed
    2 / 86 (2.33%)
    6 / 87 (6.90%)
         occurrences all number
    2
    7
    Nausea
         subjects affected / exposed
    23 / 86 (26.74%)
    24 / 87 (27.59%)
         occurrences all number
    43
    43
    Vomiting
         subjects affected / exposed
    18 / 86 (20.93%)
    15 / 87 (17.24%)
         occurrences all number
    29
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 86 (4.65%)
    7 / 87 (8.05%)
         occurrences all number
    4
    7
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 86 (2.33%)
    8 / 87 (9.20%)
         occurrences all number
    2
    11
    Proteinuria
         subjects affected / exposed
    4 / 86 (4.65%)
    8 / 87 (9.20%)
         occurrences all number
    4
    10
    Pyuria
         subjects affected / exposed
    2 / 86 (2.33%)
    6 / 87 (6.90%)
         occurrences all number
    2
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 86 (5.81%)
    4 / 87 (4.60%)
         occurrences all number
    5
    4
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    5 / 86 (5.81%)
    5 / 87 (5.75%)
         occurrences all number
    6
    7
    Gastroenteritis
         subjects affected / exposed
    3 / 86 (3.49%)
    5 / 87 (5.75%)
         occurrences all number
    3
    5
    Influenza
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 87 (0.00%)
         occurrences all number
    6
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 86 (6.98%)
    6 / 87 (6.90%)
         occurrences all number
    6
    6
    Urinary tract infection
         subjects affected / exposed
    6 / 86 (6.98%)
    3 / 87 (3.45%)
         occurrences all number
    8
    3
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    5 / 86 (5.81%)
    4 / 87 (4.60%)
         occurrences all number
    7
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2014
    The purpose of the amendment was to clarify exclusion criteria and provide guidance regarding dose modifications, concomitant medications, and contraception. The exclusion criteria and dose modification guidelines were updated to exclude patients with moderate and severe hepatic impairment (Child-Pugh Class B and C). In addition, guidance on treating patients who develop moderate hepatic impairment (Child-Pugh Class B) during the trial and immediate discontinuation if Stevens-Johnson syndrome occurs is provided, in alignment with the prescribing Exjade® information. Guidance was updated on the use of contraception. Effective contraception is required in alignment with the prescribing Exjade® information. Additional guidance was added regarding treatment discontinuation of patients with creatinine clearance <40 mL/min or serum creatinine >2 times the age appropriate ULN and caution should be used in patients with creatinine clearance between 40 and less than 60 mL/min, particularly in cases where there are additional risk factors that may impair renal function such as concomitant medications, dehydration, or severe infections in alignment with the prescribing Exjade® information. Guidance was added regarding the concomitant administration of deferasirox with CYP1A2 substrates that have a narrow therapeutic index and the concomitant use of bile acid sequestrants in alignment with the prescribing Exjade® information. An interim analysis was added to provide additional safety data to the Health Authorities during their review of the first FCT submission. Serum iron and total iron binding capacity (TIBC) were added to the visit evaluation schedule (VES) to further characterize Fe homeostasis status. Guidance for starting dose for patients pre-treated with deferiprone is being provided. In addition, clarifications were added regarding visit schedules, PK assessments and to correct typographical errors and inconsistencies.

    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
    For support, Contact us.
    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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