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    Clinical Trial Results:
    A Phase 1, Open-Label, Randomized, Repeat Dose, Parallel Group Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Ferric Maltol at Three Dosage Levels in Paediatric Subjects Aged 10-17 Years of Age with Iron Deficiency (with or without Anaemia)

    Summary
    EudraCT number
    		 2016-002192-10
    Trial protocol
    		 GB  
    Global end of trial date
    28 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2018
    First version publication date
    14 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ST10-01-103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03181451
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shield TX (UK) Limited
    Sponsor organisation address
    Northern Design Centre, Baltic Business Quarter, Gateshead Quays,, Gateshead, United Kingdom, NE8 3DF
    Public contact
    Clinical Operations, Shield TX (UK) Limited, 44 1915118500, clinicalsupport@shieldtherapeutics.com
    Scientific contact
    Clinical Operations, Shield TX (UK) Limited, 44 1915118500, clinicalsupport@shieldtherapeutics.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001195-PIP01-11
    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
    13 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the pharmacokinetics (PK) and iron uptake of ferric maltol (ST10) in children and adolescents (aged 10 to 17 years) after twice daily (BID) oral doses of 7.8 mg, 16.6 mg, or 30 mg for 9 days (Days 1 to 9) and a single morning dose on Day 10 through measurement of serum iron, transferrin saturation (TSAT), and plasma concentrations of maltol and maltol glucuronide
    Protection of trial subjects
    Routine recording of treatment-emergent AEs and changes in vital signs (blood pressure and heart rate) and 12-lead ECGs was conducted at study visits and clinical laboratory safety blood testing was conducted at screening and Day 10. In addition urine pregnancy testing was conducted at screening and at study visits, for females of child bearing potential.
    Background therapy
    		 There was no background therapy administered across all subject groups.
    Evidence for comparator
    		 No comparators were used in this trial.
    Actual start date of recruitment
    05 Apr 2017
    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 Kingdom: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    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)
    3
    Adolescents (12-17 years)
    34
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential patients were selected from the general population attending centres for routine care of their iron deficiency/anaemia; those interested in participating were invited for the screening visit in order to assess eligibility. Written informed consent/assent was obtained from parent/guardian & patient prior to undergoing any study procedure.

    Pre-assignment
    Screening details
    		 Subject eligibility for the study was assessed at the Screening Visit (conducted within 14 days prior to the planned Ferric Maltol dosing period for each subject).

    Pre-assignment period milestones
    Number of subjects started
    		 44 [1]
    Number of subjects completed
    		 37

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen faiilures: 7
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Provides details of all subjects screened in total (44); 7 subjects were ineligible for the trial after Screening, so 37 were enrolled.
    Period 1
    Period 1 title
    Ferric Maltol treatment period Days 1-10 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ferric Maltol 7.8mg BID
    Arm description
    		 Cohort received 7.8mg iron as Ferric Maltol BID for 9 days and a single 7.8mg dose on Day 10
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ferric Maltol 7.8mg
    Investigational medicinal product code
    ST10
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Cohort received 7.8mg iron as Ferric Maltol BID for 9 days and a single 7.8mg dose on Day 1

    Arm title
    		 Ferric Maltol 16.6mg BID
    Arm description
    		 Cohort received 16.6mg iron as Ferric Maltol BID for 9 days and a single 16.6mg dose on Day 10
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ferric Maltol 16.6mg
    Investigational medicinal product code
    ST10
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Cohort received 16.6mg iron as Ferric Maltol BID for 9 days and a single 7.8mg dose on Day 1

    Arm title
    		 Ferric Maltol 30.0mg BID
    Arm description
    		 Cohort received 30.0mg iron as Ferric Maltol BID for 9 days and a single 30.0mg dose on Day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ferric Maltol 30.0mg
    Investigational medicinal product code
    ST10
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Cohort received 30.0mg iron as Ferric Maltol BID for 9 days and a single 30.0mg dose on Day 10.

    Number of subjects in period 1
    		Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Started
    12
    13
    12
    Completed
    12
    11
    12
    Not completed
    0
    2
    0
         Consent withdrawn by subject
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ferric Maltol treatment period Days 1-10
    Reporting group description
    		 -

    Reporting group values
    		 Ferric Maltol treatment period Days 1-10 Total
    Number of subjects
    		 37 37
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 3 3
        Adults (18-64 years)
    		 34 34
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.0 ± 1.8 -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 13 13
    Subject analysis sets

    Subject analysis set title
    PPK Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS/ ITT Population included all subjects who took at least 1 dose of study drug and had at least 1 evaluable postdose PK sample. This population was used in the PPK analysis.

    Subject analysis sets values
    		 PPK Analysis
    Number of subjects
    37
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    3
        Adolescents (12-17 years)
    34
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.0 ± 1.8
    Gender categorical
    Units: Subjects
        Female
    24
        Male
    13

    End points

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    End points reporting groups
    Reporting group title
    Ferric Maltol 7.8mg BID
    Reporting group description
    		 Cohort received 7.8mg iron as Ferric Maltol BID for 9 days and a single 7.8mg dose on Day 10

    Reporting group title
    Ferric Maltol 16.6mg BID
    Reporting group description
    		 Cohort received 16.6mg iron as Ferric Maltol BID for 9 days and a single 16.6mg dose on Day 10

    Reporting group title
    Ferric Maltol 30.0mg BID
    Reporting group description
    		 Cohort received 30.0mg iron as Ferric Maltol BID for 9 days and a single 30.0mg dose on Day 1

    Subject analysis set title
    PPK Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS/ ITT Population included all subjects who took at least 1 dose of study drug and had at least 1 evaluable postdose PK sample. This population was used in the PPK analysis.

    Primary: Cmax Day 1 for Maltol Glucuronide

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    End point title
    		 Cmax Day 1 for Maltol Glucuronide [1]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    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: As per the statistical analysis plan (SAP), only summary descriptive statistics were derived for this end point from population PK analysis; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: mg/L
        arithmetic mean (standard deviation)
    0.5299 ± 0.5295
    1.1632 ± 0.184
    2.451 ± 2.2351
    No statistical analyses for this end point

    Primary: Serum Iron - Change from Cmax to Ctrough on Day 1

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    End point title
    		 Serum Iron - Change from Cmax to Ctrough on Day 1 [2]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1.
    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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: mg/L
        arithmetic mean (standard deviation)
    0.2715 ± 0.11873
    0.4102 ± 0.22155
    0.6169 ± 0.3230
    No statistical analyses for this end point

    Primary: Serum Iron - AUC0-6h Day 1

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    End point title
    		 Serum Iron - AUC0-6h Day 1 [3]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    Notes
    [3] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: h.mg/L
        arithmetic mean (standard deviation)
    3.928 ± 1.1318
    5.963 ± 1.7793
    6.711 ± 2.5721
    Attachments
    		 Serum Iron PPK - Day 1
    No statistical analyses for this end point

    Primary: Serum Iron - CL/F Day 1

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    End point title
    		 Serum Iron - CL/F Day 1 [4]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: L/h
        arithmetic mean (standard deviation)
    0.324 ± 0.1517
    0.654 ± 0.2441
    1.321 ± 0.6945
    No statistical analyses for this end point

    Primary: Serum Iron - V/F Day 1

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    End point title
    		 Serum Iron - V/F Day 1 [5]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: Litres
        arithmetic mean (standard deviation)
    10.462 ± 3.1033
    14.244 ± 4.8183
    22.114 ± 7.2315
    No statistical analyses for this end point

    Primary: Serum Iron - Change from Cmax to Ctrough on Day 10

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    End point title
    		 Serum Iron - Change from Cmax to Ctrough on Day 10 [6]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10
    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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: mg/L
        arithmetic mean (standard deviation)
    0.2551 ± 0.08
    0.3625 ± 0.153
    0.5486 ± 0.323
    No statistical analyses for this end point

    Primary: Serum Iron - Cave (0-6h) Day 10

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    End point title
    		 Serum Iron - Cave (0-6h) Day 10 [7]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: mg/L
        arithmetic mean (standard deviation)
    0.9748 ± 0.39783
    0.9557 ± 0.2964
    1.1667 ± 0.6142
    No statistical analyses for this end point

    Primary: Serum Iron - AUC0-6h Day 10

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    End point title
    		 Serum Iron - AUC0-6h Day 10 [8]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    Notes
    [8] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: h.mg/L
        arithmetic mean (standard deviation)
    5.849 ± 2.38
    5.734 ± 1.78
    7.00 ± 3.69
    Attachments
    		 Serum Iron PPK - Day 10
    No statistical analyses for this end point

    Primary: Serum Iron - CLss/F Day 10

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    End point title
    		 Serum Iron - CLss/F Day 10 [9]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10
    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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: L/h
        arithmetic mean (standard deviation)
    0.898 ± 0.31
    1.757 ± 0.6673
    3.264 ± 2.2297
    No statistical analyses for this end point

    Primary: Serum Iron - RAUC(0-6h) Day 10/Day 1

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    End point title
    		 Serum Iron - RAUC(0-6h) Day 10/Day 1 [10]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first and last dose of Ferric Maltol on Day 1 & Day 10
    Notes
    [10] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: Ratio - AUC(0-6h) first / last dose
        arithmetic mean (standard deviation)
    1.529 ± 1.4673
    1.020 ± 0.3170
    1.038 ± 0.3973
    No statistical analyses for this end point

    Primary: Transferrin Saturation (TSAT%) Day 1, baseline

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    End point title
    		 Transferrin Saturation (TSAT%) Day 1, baseline [11]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    Notes
    [11] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: percent
        arithmetic mean (standard deviation)
    11.5 ± 5.66
    16.8 ± 9.25
    15.8 ± 9.31
    No statistical analyses for this end point

    Primary: Transferrin Saturation (TSAT%) Day 1, maximum response (%)

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    End point title
    		 Transferrin Saturation (TSAT%) Day 1, maximum response (%) [12]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    Notes
    [12] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: percent
        arithmetic mean (standard deviation)
    18.68 ± 7.13
    28.261 ± 8.4784
    32.845 ± 10.5913
    No statistical analyses for this end point

    Primary: Transferrin Saturation (TSAT%) Day 1, time to maximum response Tmax (h).

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    End point title
    		 Transferrin Saturation (TSAT%) Day 1, time to maximum response Tmax (h). [13]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1.
    Notes
    [13] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: hour
        median (full range (min-max))
    4.00 (2.00 to 4.00)
    3.00 (2.00 to 4.00)
    3.00 (3.00 to 5.00)
    No statistical analyses for this end point

    Primary: Transferrin Saturation (TSAT%) Day 1, AUC0-6h (h.%)

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    End point title
    		 Transferrin Saturation (TSAT%) Day 1, AUC0-6h (h.%) [14]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1.
    Notes
    [14] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: h.%
        arithmetic mean (standard deviation)
    104.5 ± 41.009
    158.21 ± 50.723
    179.47 ± 60.259
    No statistical analyses for this end point

    Primary: Transferrin Saturation (TSAT%) Day 10, maximum response (%)

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    End point title
    		 Transferrin Saturation (TSAT%) Day 10, maximum response (%) [15]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    Notes
    [15] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: percent
        arithmetic mean (standard deviation)
    27.779 ± 13.86
    27.214 ± 6.699
    33.524 ± 13.633
    No statistical analyses for this end point

    Primary: Transferrin Saturation (TSAT%) Day 10, time to maximum response Tmax (h).

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    End point title
    		 Transferrin Saturation (TSAT%) Day 10, time to maximum response Tmax (h). [16]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    Notes
    [16] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: hour
        median (full range (min-max))
    3.00 (0.00 to 4.00)
    3.00 (0.00 to 4.00)
    3.00 (0.00 to 4.00)
    No statistical analyses for this end point

    Primary: Transferrin Saturation (TSAT%) Day 10, AUC0-6h (h.%).

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    End point title
    		 Transferrin Saturation (TSAT%) Day 10, AUC0-6h (h.%). [17]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    Notes
    [17] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: h.%
        arithmetic mean (standard deviation)
    157.43 ± 81.693
    149.40 ± 37.8
    180.14 ± 76.19
    No statistical analyses for this end point

    Primary: Cmax Day 10 for Maltol Glucuronide

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    End point title
    		 Cmax Day 10 for Maltol Glucuronide [18]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10
    Notes
    [18] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: mg/L
        arithmetic mean (standard deviation)
    0.9926 ± 0.023
    2.1028 ± 0.133
    4.2355 ± 0.781
    No statistical analyses for this end point

    Primary: Tmax Day 1 for Maltol Glucuronide

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    End point title
    		 Tmax Day 1 for Maltol Glucuronide [19]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    Notes
    [19] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: hour
        median (full range (min-max))
    1.00 (1.0 to 1.00)
    1.00 (0.75 to 1.00)
    1.00 (0.75 to 1.00)
    No statistical analyses for this end point

    Primary: Tmax Day 10 for Maltol Glucuronide

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    End point title
    		 Tmax Day 10 for Maltol Glucuronide [20]
    End point description
    Measured after last dose of Ferric Maltol on Day 10.
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    Notes
    [20] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: hour
        median (full range (min-max))
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
    No statistical analyses for this end point

    Primary: AUC0-6h Day 1 for Maltol Glucuronide

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    End point title
    		 AUC0-6h Day 1 for Maltol Glucuronide [21]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1.
    Notes
    [21] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: h.mg/L
        arithmetic mean (standard deviation)
    2.585 ± 0.0968
    5.613 ± 0.7589
    11.09 ± 3.9033
    Attachments
    		 Maltol Glucuronide PPK - Day 1
    No statistical analyses for this end point

    Primary: AUC0-6h Day 10 for Maltol Glucuronide

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    End point title
    		 AUC0-6h Day 10 for Maltol Glucuronide [22]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    Notes
    [22] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: h.mg/L
        arithmetic mean (standard deviation)
    5.016 ± 0.1133
    10.518 ± 0.5277
    20.511 ± 1.7997
    Attachments
    		 Maltol Glucuronide PPK - Day 10
    No statistical analyses for this end point

    Primary: AUC0-inf Day 1 for Maltol Glucuronide

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    End point title
    		 AUC0-inf Day 1 for Maltol Glucuronide [23]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after first dose of Ferric Maltol on Day 1
    Notes
    [23] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: h.mg/L
        arithmetic mean (standard deviation)
    8.590 ± 0.2025
    17.862 ± 0.9328
    34.372 ± 4.5052
    No statistical analyses for this end point

    Primary: AUC0-tau Day 10 for Maltol Glucuronide

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    End point title
    		 AUC0-tau Day 10 for Maltol Glucuronide [24]
    End point description
    End point type
    Primary
    End point timeframe
    Measured after last dose of Ferric Maltol on Day 10.
    Notes
    [24] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: h.mg/L
        arithmetic mean (standard deviation)
    8.59 ± 0.2024
    17.862 ± 0.9327
    34.368 ± 4.4981
    No statistical analyses for this end point

    Primary: RAUC(0-6h) Maltol Glucuronide Day 10/Day 1

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    End point title
    		 RAUC(0-6h) Maltol Glucuronide Day 10/Day 1 [25]
    End point description
    End point type
    Primary
    End point timeframe
    Ratio AUC0-6h measured after last dose of Ferric Maltol on Day 10 vs first dose Day 1.
    Notes
    [25] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: Ratio AUC(0-6h) Day 10/Day 1
        arithmetic mean (standard deviation)
    1.942 ± 0.0582
    1.899 ± 0.2286
    2.030 ± 0.6695
    No statistical analyses for this end point

    Primary: RCmax Maltol Glucuronide Day 10/Day 1

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    End point title
    		 RCmax Maltol Glucuronide Day 10/Day 1 [26]
    End point description
    End point type
    Primary
    End point timeframe
    Ratio Cmax measured after last dose of Ferric Maltol on Day 10 vs first dose Day 1.
    Notes
    [26] - 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: As per the study statistical analysis plan, only summary descriptive statistics were derived for this population PK endpoint; between dose-group statistical comparisons were considered inappropriate for the study design and sample size.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: Ratio Cmax Day 10/Day 1
        arithmetic mean (standard deviation)
    1.875 ± 0.0537
    1.836 ± 0.2109
    1.956 ± 0.6210
    No statistical analyses for this end point

    Secondary: Change from Baseline to Day 10 in Haemoglobin Concentration

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    End point title
    		 Change from Baseline to Day 10 in Haemoglobin Concentration
    End point description
    End point type
    Secondary
    End point timeframe
    Change calculated as difference in values measured at Screening (Baseline) and on Day 10
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: g/dL
        arithmetic mean (standard deviation)
    -0.45 ± 0.301
    -0.33 ± 1.097
    -0.03 ± 0.789
    No statistical analyses for this end point

    Secondary: Change from Baseline to Day 10 in Absolute Reticulocyte Count

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    End point title
    		 Change from Baseline to Day 10 in Absolute Reticulocyte Count
    End point description
    End point type
    Secondary
    End point timeframe
    Change calculated as difference in values measured at Screening (Baseline) and on Day 10.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    5
    10
    5
    Units: 10^12/L
        arithmetic mean (standard deviation)
    0.016 ± 0.0358
    -0.001 ± 0.0218
    0.036 ± 0.0114
    No statistical analyses for this end point

    Secondary: Negative and Positive Non-Transferrin Bound Iron [NTBI] tests on Day 10, predose

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    End point title
    		 Negative and Positive Non-Transferrin Bound Iron [NTBI] tests on Day 10, predose
    End point description
    End point type
    Secondary
    End point timeframe
    Measured prior to last dose of Ferric Maltol on Day 10
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    10
    11
    12
    Units: subjects
        Negative
    10
    11
    11
        Positive
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Negative and Positive Non-Transferrin Bound Iron [NTBI] tests on Day 1, predose

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    End point title
    		 Negative and Positive Non-Transferrin Bound Iron [NTBI] tests on Day 1, predose
    End point description
    End point type
    Secondary
    End point timeframe
    Measured prior to first dose of Ferric Maltol on Day 1.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    12
    13
    12
    Units: subjects
        Negative
    12
    13
    12
        Positive
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Ferritin - change from Baseline to Day 10, predose

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    End point title
    		 Ferritin - change from Baseline to Day 10, predose
    End point description
    End point type
    Secondary
    End point timeframe
    Change calculated as difference in values measured at Day 1, predose (Baseline) and on Day 10, predose.
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    12
    Units: µg/L
        arithmetic mean (standard deviation)
    0.5 ± 4.95
    4.1 ± 3.73
    7.3 ± 8.22
    No statistical analyses for this end point

    Secondary: TIBC - change from Baseline to Day 10, predose

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    End point title
    		 TIBC - change from Baseline to Day 10, predose
    End point description
    End point type
    Secondary
    End point timeframe
    Change calculated as difference in values measured at Day 1, predose (Baseline) and on Day 10, predose
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    10
    Units: umol/L
        arithmetic mean (standard deviation)
    1.13 ± 4.452
    -3.11 ± 3.201
    -2.12 ± 3.406
    No statistical analyses for this end point

    Secondary: UIBC - change from Baseline to Day 10, predose

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    End point title
    		 UIBC - change from Baseline to Day 10, predose
    End point description
    End point type
    Secondary
    End point timeframe
    Change calculated as difference in values measured at Day 1, predose (Baseline) and on Day 10, predose
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    11
    Units: umol/L
        arithmetic mean (standard deviation)
    -4.49 ± 8.343
    -2.33 ± 5.525
    -2.10 ± 7.775
    No statistical analyses for this end point

    Secondary: Transferrin - change from Baseline to Day 10, predose

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    End point title
    		 Transferrin - change from Baseline to Day 10, predose
    End point description
    End point type
    Secondary
    End point timeframe
    Change calculated as difference in values measured at Day 1, predose (Baseline) and on Day 10, predose
    End point values
    		 Ferric Maltol 7.8mg BID Ferric Maltol 16.6mg BID Ferric Maltol 30.0mg BID
    Number of subjects analysed
    11
    11
    11
    Units: g/L
        arithmetic mean (standard deviation)
    0.032 ± 0.2275
    -0.147 ± 0.1419
    -0.085 ± 0.151
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were solicited at each study visit after informed consent at Screening; AEs/SAEs that occurred throughout the study, up to 2 weeks after last dose of study drug (SAEs only) were recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Ferric Maltol 7.8mg BID - Safety Population
    Reporting group description
    		 Safety population adverse events for Ferric Maltol 7.8mg BID treatment arm.

    Reporting group title
    Ferric Maltol 16.6mg BID - Safety Population
    Reporting group description
    		 -

    Reporting group title
    Ferric Maltol 30.0mg BID - Safety Population
    Reporting group description
    		 -

    Serious adverse events
    		 Ferric Maltol 7.8mg BID - Safety Population Ferric Maltol 16.6mg BID - Safety Population Ferric Maltol 30.0mg BID - Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ferric Maltol 7.8mg BID - Safety Population Ferric Maltol 16.6mg BID - Safety Population Ferric Maltol 30.0mg BID - Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 12 (58.33%)
    7 / 13 (53.85%)
    7 / 12 (58.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 13 (23.08%)
    5 / 12 (41.67%)
         occurrences all number
    1
    3
    5
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    Faeces discoloured
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    3 / 12 (25.00%)
         occurrences all number
    1
    1
    3
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2017
    Protocol Version 3, dated 08 Feb 2017 MAJOR CHANGES 1. Changes to Inclusion Criteria (Section 7.3.1) Inclusion Criterion 5 Now reads: Where appropriate, female subjects of childbearing potential must agree to use a reliable method of contraception until study completion and for at least 4 weeks following their final study visit. Reliable contraception is defined as a method which results in a low failure rate, i.e., less than 1% per year when used consistently and correctly, such as implants, injectables, some intrauterine contraceptive devices (IUDs), complete sexual abstinence, a vasectomized partner and oral contraceptive medications. Rationale: Based on the initial review of MHRA on the protocol, the less than 1% per year failure rate considered to be highly effective method, therefore required to be listed in the protocol. The acceptable contraceptive methods are now listed and in line with the Clinical Trials Facilitation Group (CTFG) guidance document. Other sections within the study protocol that are affected by these changes include: Section 4, Synopsis, Inclusion Criteria. 2. Changes to Continuation of Treatment (Section 8.8) Now reads: No further provisions are made for access to the study treatment under this protocol following Visit 3, Day 10. Rationale: Further to internal discussions, Shield concluded that it is not beneficial to continue treatment with the lower dose strengths for which no data is available and efficacy unknown. This is a phase 1 study designed to establish the PK using the approved 30mg capsules and 2 lower doses. The data will be used to select the dose for a subsequent Phase 3 paediatric study which will be conducted for a longer duration.

    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 specified.
    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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