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    Clinical Trial Results:
    A randomized, open label, six sequences, cross-over study in healthy Japanese subjects to evaluate the pharmacokinetic comparability of deferasirox granule formulation with the reference dispersible tablet formulation (Exjade) 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
    		 2016-000308-28
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2018
    First version publication date
    11 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CICL670F1102
    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 613421111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613421111,
    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
    10 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of Part 1 was to evaluate the PK comparability of two different doses of the deferasirox (DFX) granule formulation in comparison to the reference dispersible formulation (Exjade®) in healthy Japanese subjects under fasted conditions. Per amendment, part 2 was added where the primary objective was to evaluate the PK comparability of 900 mg DFX granule formulation in comparison to the reference dispersible formulation (1500 mg) in healthy Japanese subjects under fasted conditions.
    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
    27 Jun 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
    Japan: 193
    Worldwide total number of subjects
    193
    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)
    193
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized to 1 of 6 treatment groups in Part 1. In Part 2, participants were randomized to 1 of 2 treatment groups.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 - Arm A/B/C
    Arm description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 990 mg of deferasirox granule formuklation orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment A
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Investigational medicinal product name
    Treatment B
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Investigational medicinal product name
    Treatment C
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 19, participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Arm title
    		 Part 1 - Arm A/C/B
    Arm description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally.On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment A
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Investigational medicinal product name
    Treatment C
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Investigational medicinal product name
    Treatment B
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Arm title
    		 Part 1 - Arm B/A/C
    Arm description
    		 On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 19, participants received a single dose of 990 mg of deferasirox granule formulation orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment B
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Investigational medicinal product name
    Treatment A
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Investigational medicinal product name
    Treatment C
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 19, participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Arm title
    		 Part 1 - Arm B/C/A
    Arm description
    		 On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment B
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Investigational medicinal product name
    Treatment C
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally

    Investigational medicinal product name
    Treatment A
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Arm title
    		 Part 1 - ARM C/A/B
    Arm description
    		 On day 1, participants received a single dose of 990 mg of deferasirox granule formuklation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment C
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 990 mg of deferasirox granule formuklation orally.

    Investigational medicinal product name
    Treatment A
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Investigational medicinal product name
    Treatment B
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Arm title
    		 Part 1 - Arm C/B/A
    Arm description
    		 On day 1, participants received a single dose of 990 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment C
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Investigational medicinal product name
    Treatment B
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Investigational medicinal product name
    Treatment A
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Arm title
    		 Part 2 - Arm D/E
    Arm description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 900 mg of deferasirox granule formulation orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment D
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Investigational medicinal product name
    Treatment E
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 900 mg of deferasirox granule formulation orally.

    Arm title
    		 Part 2 - Arm E/D
    Arm description
    		 On day 1, participants received a single dose of 900 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treatment E
    Investigational medicinal product code
    Other name
    Deferasirox
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1, participants received a single dose of 900 mg of deferasirox granule formulation orally.

    Investigational medicinal product name
    Treatment D
    Investigational medicinal product code
    ICL670
    Other name
    Deferasirox
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Number of subjects in period 1
    		Part 1 - Arm A/B/C Part 1 - Arm A/C/B Part 1 - Arm B/A/C Part 1 - Arm B/C/A Part 1 - ARM C/A/B Part 1 - Arm C/B/A Part 2 - Arm D/E Part 2 - Arm E/D
    Started
    17
    16
    16
    16
    16
    16
    48
    48
    PK analysis set
    17
    16
    16
    16
    16
    16
    48
    48
    Completed
    16
    16
    16
    14
    16
    15
    47
    48
    Not completed
    1
    0
    0
    2
    0
    1
    1
    0
         Physician decision
    1
    -
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    1
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 - Arm A/B/C
    Reporting group description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 990 mg of deferasirox granule formuklation orally.

    Reporting group title
    Part 1 - Arm A/C/B
    Reporting group description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally.On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 1 - Arm B/A/C
    Reporting group description
    		 On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 19, participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 1 - Arm B/C/A
    Reporting group description
    		 On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally

    Reporting group title
    Part 1 - ARM C/A/B
    Reporting group description
    		 On day 1, participants received a single dose of 990 mg of deferasirox granule formuklation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 1 - Arm C/B/A
    Reporting group description
    		 On day 1, participants received a single dose of 990 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Reporting group title
    Part 2 - Arm D/E
    Reporting group description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 900 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 2 - Arm E/D
    Reporting group description
    		 On day 1, participants received a single dose of 900 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Reporting group values
    		 Part 1 - Arm A/B/C Part 1 - Arm A/C/B Part 1 - Arm B/A/C Part 1 - Arm B/C/A Part 1 - ARM C/A/B Part 1 - Arm C/B/A Part 2 - Arm D/E Part 2 - Arm E/D Total
    Number of subjects
    		 17 16 16 16 16 16 48 48 193
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 17 16 16 16 16 16 48 48 193
        From 65-84 years
    		 0 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 27.6 ± 6.95 30 ± 7.41 28.1 ± 6.01 29 ± 8.09 32.2 ± 9.01 30.6 ± 8.14 32.2 ± 7.74 30.9 ± 8.4 -
    Gender, Male/Female
    Units: Participants
        Female
    		 1 1 1 1 1 1 0 0 6
        Male
    		 16 15 15 15 15 15 48 48 187

    End points

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    End points reporting groups
    Reporting group title
    Part 1 - Arm A/B/C
    Reporting group description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 990 mg of deferasirox granule formuklation orally.

    Reporting group title
    Part 1 - Arm A/C/B
    Reporting group description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally.On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 1 - Arm B/A/C
    Reporting group description
    		 On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 19, participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 1 - Arm B/C/A
    Reporting group description
    		 On day 1, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 990 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally

    Reporting group title
    Part 1 - ARM C/A/B
    Reporting group description
    		 On day 1, participants received a single dose of 990 mg of deferasirox granule formuklation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 19, participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 1 - Arm C/B/A
    Reporting group description
    		 On day 1, participants received a single dose of 990 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1080 mg of deferasirox granule formulation orally. On day 19, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Reporting group title
    Part 2 - Arm D/E
    Reporting group description
    		 On day 1, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally. On day 10, participants received a single dose of 900 mg of deferasirox granule formulation orally.

    Reporting group title
    Part 2 - Arm E/D
    Reporting group description
    		 On day 1, participants received a single dose of 900 mg of deferasirox granule formulation orally. On day 10, participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Subject analysis set title
    Part 1 - Treatment A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Subject analysis set title
    Part 1 - Treatment B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Subject analysis set title
    Part 1 - Treatment C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Subject analysis set title
    Part 1 - Treatment A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Subject analysis set title
    Part 1 - Treatment B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1080 mg of deferasirox granule formulation orally.

    Subject analysis set title
    Part 1 - Treatment C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 990 mg of deferasirox granule formulation orally.

    Subject analysis set title
    Part 2 -Treatment D
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Subject analysis set title
    Part 2 - Treatment E
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 900 mg of deferasirox granule formulation orally.

    Subject analysis set title
    Part 2 -Treatment D
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Subject analysis set title
    Part 2 - Treatment E
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 900 mg of deferasirox granule formulation orally.

    Subject analysis set title
    Part 2 - Treatment D
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Subject analysis set title
    Part 2 - Treatment D
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a single dose of 1500 mg dispersible tablet formulation of deferasirox orally.

    Primary: Part 1 - Summary of PK parameter: area under the curve from time zero to infinity (AUCinf)

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    End point title
    		 Part 1 - Summary of PK parameter: area under the curve from time zero to infinity (AUCinf)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Primary
    End point timeframe
    Days 1, 10, 19 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 1 - Treatment A Part 1 - Treatment B Part 1 - Treatment C
    Number of subjects analysed
    88
    93
    93
    Units: umol/L*hr
        arithmetic mean (standard deviation)
    1790 ± 596
    1940 ± 552
    1780 ± 505
    Statistical analysis title
    		 AUCinf treatment comparison between A and B
    Comparison groups
    Part 1 - Treatment A v Part 1 - Treatment B
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.0954
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.0479
         upper limit
    		 1.1451
    Statistical analysis title
    		 AUCinf treatment comparison between A and C
    Comparison groups
    Part 1 - Treatment A v Part 1 - Treatment C
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.0048
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9612
         upper limit
    		 1.0503

    Primary: Part 1 - Summary of PK parameter: area under the curve from time zero to last measurable concentration sampling time (AUClast)

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    End point title
    		 Part 1 - Summary of PK parameter: area under the curve from time zero to last measurable concentration sampling time (AUClast)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Primary
    End point timeframe
    Days 1, 10, 19 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 1 - Treatment A Part 1 - Treatment B Part 1 - Treatment C
    Number of subjects analysed
    94
    94
    94
    Units: umol/L*hr
        arithmetic mean (standard deviation)
    1710 ± 524
    1870 ± 518
    1690 ± 484
    Statistical analysis title
    		 AUClast treatment comparison between A and B
    Comparison groups
    Part 1 - Treatment A v Part 1 - Treatment B
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.0994
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.0546
         upper limit
    		 1.1461
    Statistical analysis title
    		 AUClast treatment comparison between A and C
    Comparison groups
    Part 1 - Treatment A v Part 1 - Treatment C
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.9984
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9577
         upper limit
    		 1.0408

    Primary: Part 1 - Summary of PK parameter: maximum (peak) observed plasma concentration after single dose administration (Cmax)

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    End point title
    		 Part 1 - Summary of PK parameter: maximum (peak) observed plasma concentration after single dose administration (Cmax)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Primary
    End point timeframe
    Days 1, 10, 19 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 1 - Treatment A Part 1 - Treatment B Part 1 - Treatment C
    Number of subjects analysed
    94
    94
    94
    Units: umol/L
        arithmetic mean (standard deviation)
    96.6 ± 26.7
    130 ± 37.7
    120 ± 33.5
    Statistical analysis title
    		 Cmax treatment comparison between A and B
    Comparison groups
    Part 1 - Treatment A v Part 1 - Treatment B
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.3398
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2794
         upper limit
    		 1.403
    Statistical analysis title
    		 Cmax treatment comparison between A and C
    Comparison groups
    Part 1 - Treatment A v Part 1 - Treatment C
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.2432
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1872
         upper limit
    		 1.3019

    Primary: Part 2 - Summary of PK parameter: area under the curve from time zero to infinity (AUCinf)

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    End point title
    		 Part 2 - Summary of PK parameter: area under the curve from time zero to infinity (AUCinf)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Primary
    End point timeframe
    Days 1 and 10 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 2 -Treatment D Part 2 - Treatment E
    Number of subjects analysed
    79
    87
    Units: umol/L*hr
        arithmetic mean (standard deviation)
    1830 ± 611
    1800 ± 511
    Statistical analysis title
    		 AUCinf treatment comparison between D and E
    Comparison groups
    Part 2 -Treatment D v Part 2 - Treatment E
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.9708
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.929
         upper limit
    		 1.0144

    Primary: Part 2 - Summary of PK parameter: area under the curve from time zero to last measurable concentration sampling time (AUClast)

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    End point title
    		 Part 2 - Summary of PK parameter: area under the curve from time zero to last measurable concentration sampling time (AUClast)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Primary
    End point timeframe
    Days 1 and 10 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 2 -Treatment D Part 2 - Treatment E
    Number of subjects analysed
    96
    95
    Units: umol/L*hr
        arithmetic mean (standard deviation)
    1810 ± 561
    1720 ± 452
    Statistical analysis title
    		 AUClast treatment comparison between D and E
    Comparison groups
    Part 2 -Treatment D v Part 2 - Treatment E
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.9546
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9196
         upper limit
    		 0.9909

    Primary: Part 2 - Summary of PK parameter: maximum (peak) observed plasma concentration after single dose administration (Cmax)

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    End point title
    		 Part 2 - Summary of PK parameter: maximum (peak) observed plasma concentration after single dose administration (Cmax)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Primary
    End point timeframe
    Days 1 and 10 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 2 -Treatment D Part 2 - Treatment E
    Number of subjects analysed
    96
    95
    Units: umol/L
        arithmetic mean (standard deviation)
    97.1 ± 24.8
    116 ± 31.4
    Statistical analysis title
    		 Cmax treatment comparison between D and E
    Comparison groups
    Part 2 -Treatment D v Part 2 - Treatment E
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.1895
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.1382
         upper limit
    		 1.2431

    Secondary: Part 1 - Summary of PK parameter: time to reach maximum (peak) plasma concentration after single dose administration (Tmax)

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    End point title
    		 Part 1 - Summary of PK parameter: time to reach maximum (peak) plasma concentration after single dose administration (Tmax)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1, 10, 19 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 1 - Treatment A Part 1 - Treatment B Part 1 - Treatment C
    Number of subjects analysed
    94
    94
    94
    Units: hour
        median (full range (min-max))
    4 (1.5 to 6)
    4 (1.5 to 8)
    3 (1.5 to 8)
    No statistical analyses for this end point

    Secondary: Part 1 - Summary of PK parameter: elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic concentration-time curve (T1/2)

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    End point title
    		 Part 1 - Summary of PK parameter: elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic concentration-time curve (T1/2)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1, 10, 19 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 1 - Treatment B Part 1 - Treatment C Part 1 - Treatment A
    Number of subjects analysed
    93
    93
    94
    Units: hour
        arithmetic mean (standard deviation)
    14.8 ± 5.35
    15.5 ± 6.13
    16.9 ± 9.54
    No statistical analyses for this end point

    Secondary: Part 1 - Summary of PK parameter: the mean residence time from time of dosing to the last measurable concentration sampling time (MRTlast)

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    End point title
    		 Part 1 - Summary of PK parameter: the mean residence time from time of dosing to the last measurable concentration sampling time (MRTlast)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1, 10, 19 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 1 - Treatment A Part 1 - Treatment B Part 1 - Treatment C
    Number of subjects analysed
    94
    94
    94
    Units: hour
        arithmetic mean (standard deviation)
    19 ± 3.9
    16.9 ± 3.11
    16.8 ± 3.1
    No statistical analyses for this end point

    Secondary: Part - 1 Summary of PK parameter: terminal slope of elimination phase (Lambda_z)

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    End point title
    		 Part - 1 Summary of PK parameter: terminal slope of elimination phase (Lambda_z)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1, 10, 19 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 1 - Treatment B Part 1 - Treatment C Part 1 - Treatment A
    Number of subjects analysed
    93
    93
    94
    Units: 1/hr
        arithmetic mean (standard deviation)
    0.0513 ± 0.0139
    0.0508 ± 0.0168
    0.0489 ± 0.017
    No statistical analyses for this end point

    Secondary: Part 2 - Summary of PK parameter: time to reach maximum (peak) plasma concentration after single dose administration (Tmax)

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    End point title
    		 Part 2 - Summary of PK parameter: time to reach maximum (peak) plasma concentration after single dose administration (Tmax)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1 and 10 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 2 - Treatment E Part 2 - Treatment D
    Number of subjects analysed
    95
    96
    Units: hour
        median (full range (min-max))
    3 (1.5 to 8)
    4 (1 to 8)
    No statistical analyses for this end point

    Secondary: Part 2 - Summary of PK parameter: elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic concentration-time curve (T1/2)

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    End point title
    		 Part 2 - Summary of PK parameter: elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic concentration-time curve (T1/2)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1 and 10 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 2 - Treatment E Part 2 - Treatment D
    Number of subjects analysed
    95
    89
    Units: hour
        arithmetic mean (standard deviation)
    18.1 ± 9.69
    23.4 ± 34.4
    No statistical analyses for this end point

    Secondary: Part 2 - Summary of PK parameter: mean residence time from time of dosing to the last measurable concentration sampling time (MRTlast)

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    End point title
    		 Part 2 - Summary of PK parameter: mean residence time from time of dosing to the last measurable concentration sampling time (MRTlast)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1 and 10 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 2 - Treatment E Part 2 - Treatment D
    Number of subjects analysed
    95
    96
    Units: hour
        arithmetic mean (standard deviation)
    18.3 ± 3.37
    20.3 ± 4.27
    No statistical analyses for this end point

    Secondary: Part - 2 Summary of PK parameter: terminal slope of elimination phase (Lambda_z)

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    End point title
    		 Part - 2 Summary of PK parameter: terminal slope of elimination phase (Lambda_z)
    End point description
    Serial blood samples for plasma deferasirox concentration were collected to analyze PK parameters.
    End point type
    Secondary
    End point timeframe
    Days 1 and 10 at 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 46, 8, 12, 24,36, 48 and 72 hours post-dose.
    End point values
    		 Part 2 - Treatment E Part 2 - Treatment D
    Number of subjects analysed
    95
    89
    Units: 1/hour
        arithmetic mean (standard deviation)
    0.0452 ± 0.0152
    0.0433 ± 0.0162
    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
    16.1
    Reporting groups
    Reporting group title
    Arm A/B/C
    Reporting group description
    		 A/B/C

    Reporting group title
    Arm A/C/B
    Reporting group description
    		 A/C/B

    Reporting group title
    Arm B/A/C
    Reporting group description
    		 B/A/C

    Reporting group title
    Arm B/C/A
    Reporting group description
    		 B/C/A

    Reporting group title
    Arm C/A/B
    Reporting group description
    		 C/A/B

    Reporting group title
    Arm C/B/A
    Reporting group description
    		 C/B/A

    Reporting group title
    Arm D/E
    Reporting group description
    		 D/E

    Reporting group title
    Arm E/D
    Reporting group description
    		 E/D

    Serious adverse events
    		 Arm A/B/C Arm A/C/B Arm B/A/C Arm B/C/A Arm C/A/B Arm C/B/A Arm D/E Arm E/D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A/B/C Arm A/C/B Arm B/A/C Arm B/C/A Arm C/A/B Arm C/B/A Arm D/E Arm E/D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 16 (6.25%)
    5 / 16 (31.25%)
    4 / 16 (25.00%)
    4 / 16 (25.00%)
    3 / 16 (18.75%)
    7 / 48 (14.58%)
    4 / 48 (8.33%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Protein urine present
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Urine bilirubin increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 48 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 16 (0.00%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    2 / 16 (12.50%)
    5 / 48 (10.42%)
    1 / 48 (2.08%)
         occurrences all number
    4
    0
    6
    2
    4
    3
    8
    1
    Enterocolitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2014
    Amendment 1, issued before the start of the study, was written because some of the measurement methods need to be adjusted to the actual operation in the Investigator site in Japan. In addition, the editorial changes and corrections in the protocol text and the table were made for consistency and/or clarifications. The most important changes to the protocol were:Added the description regarding water intake during drug administration under the fasted condition; changed 3 mL to 4 mL of PK blood samples; added detailed tube description because an available tube without plasma separation gel is only for 4mL blood collection in Japan; and added description of samples collection window at 12 hours post-dose.
    11 Dec 2014
    ) issued after the release of part 1 clinical study report (27-Nov-2014), because although Part 1 study demonstrated comparable bioavailability (AUC) between the reference DT at a dose of 1500 mg and the granule formulation at doses of 1080 mg and 990 mg, Cmax did not satisfy the predefined criteria i.e., Cmax of 990 mg or 1080 mg DFX granule was 24% and 34% higher compared to the 1500 mg DT treatment. Amendment 2 proposed a further reduced dose of granule formulation at 900 mg to be investigated as Part 2 of this study. The selection of 900 mg was based on simulation using data obtained in Part 1 of the current study. The most important changes to the protocol were: added the description of protocol amendment rationale; added the objective and related end-points of Part 2 study; added the description of study design of Part 2 study; added the description of study design of Part 2 study; added the description of study treatment of Part 2 study; added the description of dietary, fluid, and other restrictions of Part 2 study; added the description of treatment assignment or randomization of Part 2 study; added the description of study drug packaging and labeling of Part 2 study; added the visit schedule, assessment, and PK log table of Part 2 study; added the description of analysis sets of Part 2 study; added the description of statistical hypothesis, model, and method of analysis of Part 2 study; added the secondary objectives of Part 2 study; and added the description of sample size calculation of Part 2 study.

    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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