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    Clinical Trial Results:
    A randomized, open label, single center, phase I, two way, cross-over study to evaluate the pharmacokinetic comparability of deferasirox new granule formulation with the reference dispersible formulation in healthy subjects. Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2016-000307-93
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2018
    First version publication date
    02 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CICL670F2105
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001103-PIP01-10
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the PK comparability of a reduced dose of the deferasirox granule formulation given with a small amount of a soft food matrix (apple sauce) versus the reference dispersible tablet formulation of deferasirox under fasted conditions in healthy subjects.
    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
    29 Jul 2013
    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
    United States: 53
    Worldwide total number of subjects
    53
    EEA total number of subjects
    0
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    53
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Informed consent was obtained from each subject in writing before screening. The study was described by the Investigator or designee, who answered any questions, and written information was also provided.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 No sequence
    Arm description
    		 Those subjects that were non-compliant with the iron supplement pre-treatment, or did not meet all inclusion and exclusion criteria at the Baseline Visit or when target recruitment had been completed, were discontinued prior to randomization and were assigned to the ‘no sequence’ group.
    Arm type
    		 Supportive treatment

    Investigational medicinal product name
    ferrous sulfate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The supportive treatment was an iron supplement, ferrous sulfate 325 mg strength oral tablet, which was equivalent to 65 mg Fe++ (elemental iron).

    Arm title
    		 A/B sequence
    Arm description
    		 Treatment A: Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions. Treatment B: Single dose of 1500 mg reference DT formulation of deferasirox dispersed in 200 ml water under fasted conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    deferasirox granule formulation
    Investigational medicinal product code
    Other name
    Treatment A
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions.

    Investigational medicinal product name
    reference DT formulation
    Investigational medicinal product code
    Other name
    deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 1500 mg reference DT formulation (3 tablets of 500 mg) of deferasirox under fasted conditions dispersed in 200 ml water.

    Arm title
    		 B/A sequence
    Arm description
    		 Treatment B: Single dose of 1500 mg reference DT formulation (3 tablets of 500 mg) of deferasirox under fasted conditions dispersed in 200 ml water. Treatment A: Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    deferasirox granule formulation
    Investigational medicinal product code
    Other name
    Treatment A
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions.

    Investigational medicinal product name
    reference DT formulation
    Investigational medicinal product code
    Other name
    Treatment B
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 1500 mg reference DT formulation (3 tablets of 500 mg) of deferasirox under fasted conditions dispersed in 200 ml water.

    Number of subjects in period 1
    		No sequence A/B sequence B/A sequence
    Started
    12
    21
    20
    Completed treatment
    0
    18
    20
    Completed
    0
    18
    20
    Not completed
    12
    3
    0
         Consent withdrawn by subject
    4
    1
    -
         Administrative problems
    8
    -
    -
         Protocol deviation
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    No sequence
    Reporting group description
    		 Those subjects that were non-compliant with the iron supplement pre-treatment, or did not meet all inclusion and exclusion criteria at the Baseline Visit or when target recruitment had been completed, were discontinued prior to randomization and were assigned to the ‘no sequence’ group.

    Reporting group title
    A/B sequence
    Reporting group description
    		 Treatment A: Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions. Treatment B: Single dose of 1500 mg reference DT formulation of deferasirox dispersed in 200 ml water under fasted conditions.

    Reporting group title
    B/A sequence
    Reporting group description
    		 Treatment B: Single dose of 1500 mg reference DT formulation (3 tablets of 500 mg) of deferasirox under fasted conditions dispersed in 200 ml water. Treatment A: Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions.

    Reporting group values
    		 No sequence A/B sequence B/A sequence Total
    Number of subjects
    		 12 21 20 53
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 12 21 20 53
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28 ( 5.61 ) 31.2 ( 8.98 ) 31.5 ( 10.29 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 12 7 25
        Male
    		 6 9 13 28

    End points

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    End points reporting groups
    Reporting group title
    No sequence
    Reporting group description
    		 Those subjects that were non-compliant with the iron supplement pre-treatment, or did not meet all inclusion and exclusion criteria at the Baseline Visit or when target recruitment had been completed, were discontinued prior to randomization and were assigned to the ‘no sequence’ group.

    Reporting group title
    A/B sequence
    Reporting group description
    		 Treatment A: Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions. Treatment B: Single dose of 1500 mg reference DT formulation of deferasirox dispersed in 200 ml water under fasted conditions.

    Reporting group title
    B/A sequence
    Reporting group description
    		 Treatment B: Single dose of 1500 mg reference DT formulation (3 tablets of 500 mg) of deferasirox under fasted conditions dispersed in 200 ml water. Treatment A: Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions.

    Subject analysis set title
    Pharmacokinetic analysis set (PAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Consisted of all safety subjects who had completed the two Treatment Periods with evaluable deferasirox PK data allowing a comparison between the test formulation and the reference formulation.

    Subject analysis set title
    Deferasirox granule formulation
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment A: Single dose of 1200 mg of deferasirox granule formulation (3 stick packs of 400 mg) with apple sauce under fasted conditions

    Subject analysis set title
    Deferasirox DTs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment B: Single dose of 1500 mg reference DT formulation of deferasirox under fasted conditions dispersed in 200 ml water.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized subjects who received at least one dose of study drug (defined as either deferasirox or iron supplement). If an enrolled subject was randomized but received iron supplement only, he/she was included in the Safety Set.

    Primary: Analysis of AUCinf for plasma deferasirox by treatment

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    End point title
    		 Analysis of AUCinf for plasma deferasirox by treatment [1]
    End point description
    The area under the curve (AUC) from time zero to infinity.
    End point type
    Primary
    End point timeframe
    Days 1 through 4 and 10 to 13 of Treatment Periods 1 and 2 at the following time points: 0 (pre-dose) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 hours
    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: Analysis was done within a single arm. A comparison groups was not use for statistical analysis.
    End point values
    		 Deferasirox granule formulation Deferasirox DTs
    Number of subjects analysed
    38 [2]
    36 [3]
    Units: µmol/L*hr
        arithmetic mean (standard deviation)
    1720 ( 476 )
    1440 ( 481 )
    Notes
    [2] - Pharmacokinetic Analysis Set (PAS): safety subjects with evaluable deferasirox PK data
    [3] - number of subjects with non-missing values
    No statistical analyses for this end point

    Primary: Analysis of AUClast for plasma deferasirox by treatment

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    End point title
    		 Analysis of AUClast for plasma deferasirox by treatment [4]
    End point description
    The AUC from time zero to the last measurable concentration sampling time (Tlast)
    End point type
    Primary
    End point timeframe
    Days 1 through 4 and 10 to 13 of Treatment Periods 1 and 2 at the following time points: 0 (pre-dose) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 hours
    Notes
    [4] - 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: Analysis was done within a single arm. A comparison groups was not use for statistical analysis.
    End point values
    		 Deferasirox granule formulation Deferasirox DTs
    Number of subjects analysed
    38
    38
    Units: µmol/L*hr
        arithmetic mean (standard deviation)
    1680 ( 456 )
    1380 ( 420 )
    No statistical analyses for this end point

    Primary: Analysis of Cmax for plasma deferasirox by treatment

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    End point title
    		 Analysis of Cmax for plasma deferasirox by treatment [5]
    End point description
    The maximum (peak) observed plasma concentration after single dose administration
    End point type
    Primary
    End point timeframe
    Days 1 through 4 and 10 to 13 of Treatment Periods 1 and 2 at the following time points: 0 (pre-dose) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 hours
    Notes
    [5] - 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: Analysis was done within a single arm. A comparison groups was not use for statistical analysis.
    End point values
    		 Deferasirox granule formulation Deferasirox DTs
    Number of subjects analysed
    38
    38
    Units: µmol/L
        arithmetic mean (standard deviation)
    124 ( 33.1 )
    86.8 ( 19.6 )
    No statistical analyses for this end point

    Primary: Analysis of Tmax for plasma deferasirox by treatment

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    End point title
    		 Analysis of Tmax for plasma deferasirox by treatment [6]
    End point description
    The time to reach maximum (peak) plasma concentration after single dose administration
    End point type
    Primary
    End point timeframe
    Days 1 through 4 and 10 to 13 of Treatment Periods 1 and 2 at the following time points: 0 (pre-dose) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 hours
    Notes
    [6] - 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: Analysis was done within a single arm. A comparison groups was not use for statistical analysis.
    End point values
    		 Deferasirox granule formulation Deferasirox DTs
    Number of subjects analysed
    38
    38
    Units: hr
        median (full range (min-max))
    3 (1.5 to 6)
    3 (1.5 to 4)
    No statistical analyses for this end point

    Primary: Analysis of T1/2 for plasma deferasirox by treatment

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    End point title
    		 Analysis of T1/2 for plasma deferasirox by treatment [7]
    End point description
    The elimination half-life associated with the terminal slope (lambda_z) of a semi-logarithmic concentration-time curve.
    End point type
    Primary
    End point timeframe
    Days 1 through 4 and 10 to 13 of Treatment Periods 1 and 2 at the following time points: 0 (pre-dose) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 hours
    Notes
    [7] - 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: Analysis was done within a single arm. A comparison groups was not use for statistical analysis.
    End point values
    		 Deferasirox granule formulation Deferasirox DTs
    Number of subjects analysed
    38
    36 [8]
    Units: hr
        arithmetic mean (standard deviation)
    12.5 ( 4.08 )
    14.5 ( 5.83 )
    Notes
    [8] - number of subjects with non-missing values
    No statistical analyses for this end point

    Primary: Analysis of Lambda_z for plasma deferasirox by treatment

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    End point title
    		 Analysis of Lambda_z for plasma deferasirox by treatment [9]
    End point description
    The terminal slope of elimination phase.
    End point type
    Primary
    End point timeframe
    Days 1 through 4 and 10 to 13 of Treatment Periods 1 and 2 at the following time points: 0 (pre-dose) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 hours
    Notes
    [9] - 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: Analysis was done within a single arm. A comparison groups was not use for statistical analysis.
    End point values
    		 Deferasirox granule formulation Deferasirox DTs
    Number of subjects analysed
    38
    36 [10]
    Units: 1/hr
        arithmetic mean (standard deviation)
    0.0604 ( 0.0171 )
    0.0557 ( 0.0218 )
    Notes
    [10] - number of subjects with non-missing values
    No statistical analyses for this end point

    Secondary: Percentage of participants that experienced an adverse event (AE)

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    End point title
    		 Percentage of participants that experienced an adverse event (AE)
    End point description
    End point type
    Secondary
    End point timeframe
    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.
    End point values
    		 Safety Set
    Number of subjects analysed
    41
    Units: percent
        number (not applicable)
    14.6
    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 All subjects

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 41 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 41 (14.63%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Anal haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle tightness
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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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