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    Clinical Trial Results:
    A phase I study to evaluate the pharmacokinetics, safety and tolerability of preservative free tafluprost ophthalmic solution (0.0015%) in pediatric patients diagnosed with glaucoma or ocular hypertension.

    Summary
    EudraCT number
    		 2013-004302-26
    Trial protocol
    		 GB   HU   SK   PL  
    Global end of trial date
    03 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Mar 2019
    First version publication date
    07 Mar 2019
    Other versions
    Summary report(s)
    		 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    201350
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Santen Oy
    Sponsor organisation address
    Niittyhaankatu 20, PO BOX 33, Tampere, Finland, FIN-33721
    Public contact
    Tommi Pesonen, MSc, 4Pharma Ltd, +358 22835700,
    Scientific contact
    Auli Ropo, MD, PhD, Santen Oy, Global Medical Affairs, +358 32848863,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001187-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
    20 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the pharmacokinetics (PK) of preservativefree tafluprost 0.0015% eye drops in paediatric patients of at least 36 week gestation and 1 month postnatal to under 18 years of age diagnosed with paediatric glaucoma or ocular hypertension (OHT).
    Protection of trial subjects
    This was an open-label, multicenter Phase I study in pediatric patients diagnosed with glaucoma or OHT. The planned enrollment of at least 18 pediatric patients proceeded in a sequential manner beginning with the oldest age group: First at least five 12 to <18 years old patientswere enrolled. These were followed by at least five 3 to <12 years old patients and then at least eight 1 month to <3 years old patients. A PK and safety assessment committee (PKSAC) reviewed all relevant data before patients could be enrolled to a younger age cohort. Official minutes of the PKAC meetings for these two decision-making steps were transcribed. The IECs/IRBs and health authorities were noted as appropriate. As a safeguard, individual data of the youngest age cohort was evaluated in complementary ad hoc meetings. The study medical monitor and statistician, as well as Sponsor’s representatives (from the disciplines of clinical science, PV, and PK) were the members of the PKSAC. The PI was also included in all communications and decision-making by the PKSAC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    18
    EEA total number of subjects
    5
    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)
    4
    Children (2-11 years)
    8
    Adolescents (12-17 years)
    6
    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
    		 This study was conducted at 8 centers in the United States and Europe. A total of 20 pediatric patients were screened for the study. A total of 18 patients were enrolled to this study, six patients in each age group.

    Pre-assignment
    Screening details
    		 Eligible patients were on IOP-lowering medication, or had not used it for ≥4 weeks prior to the study, or were treatment naïve. All eligible patients were assigned to receive the following open-label treatment on Day 1 for a period of 7-9 days.

    Pre-assignment period milestones
    Number of subjects started
    		 18
    Number of subjects completed
    		 18

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

    Arms
    Arm title
    		 Tafluprost 0.0015%
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    tafluprost
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ocular use
    Dosage and administration details
    The once daily dosing of tafluprost eye drops was based on the latest SmPC. Each patient received one drop of tafluprost 0.0015% once daily at 08:00 (±2h) in both eyes for 7-9 days.

    Number of subjects in period 1
    		Tafluprost 0.0015%
    Started
    18
    Completed
    17
    Not completed
    1
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 18 18
    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)
    		 4 4
        Children (2-11 years)
    		 8 8
        Adolescents (12-17 years)
    		 6 6
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.4 ( 5.73 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 9 9
    Age group
    Age group 1: 12 years to <18 years old Age group 2: 3 years to <12 years old Age group 3: 1 month to <3 years old
    Units: Subjects
        Age group 1
    		 6 6
        Age group 2
    		 6 6
        Age group 3
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Safety dataset
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients were included in the Safety dataset.

    Subject analysis set title
    PK dataset
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The patient with improper entry and the patients using the butterfly needlewere excluded from the PK dataset.

    Subject analysis sets values
    		 Safety dataset PK dataset
    Number of subjects
    18
    11
    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)
    4
    3
        Children (2-11 years)
    8
    5
        Adolescents (12-17 years)
    6
    3
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.4 ( 5.73 )
    7.3 ( 6.04 )
    Gender categorical
    Units: Subjects
        Female
    9
    4
        Male
    9
    7
    Age group
    Age group 1: 12 years to <18 years old Age group 2: 3 years to <12 years old Age group 3: 1 month to <3 years old
    Units: Subjects
        Age group 1
    6
    3
        Age group 2
    6
    3
        Age group 3
    6
    5

    End points

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    End points reporting groups
    Reporting group title
    Tafluprost 0.0015%
    Reporting group description
    		 -

    Subject analysis set title
    Safety dataset
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled patients were included in the Safety dataset.

    Subject analysis set title
    PK dataset
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The patient with improper entry and the patients using the butterfly needlewere excluded from the PK dataset.

    Primary: Pharmacokinetic parameter tmax

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    End point title
    		 Pharmacokinetic parameter tmax [1]
    End point description
    End point type
    Primary
    End point timeframe
    Tafluprost acid concentrations were measured at the end of tafluprost dosing period.
    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: The PK of tafluprost acid was characterized by pediatric age group. Thus, no formal hypotheses were set for the study. PK variables were summarized by age group.
    End point values
    		 PK dataset
    Number of subjects analysed
    11
    Units: minutes
        Age group 1
    10
        Age group 2
    10
        Age group 3
    10
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameter Cmax

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    End point title
    		 Pharmacokinetic parameter Cmax [2]
    End point description
    End point type
    Primary
    End point timeframe
    Tafluprost acid concentrations were measured at the end of tafluprost dosing period.
    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: The PK of tafluprost acid was characterized by pediatric age group. Thus, no formal hypotheses were set for the study. PK variables were summarized by age group.
    End point values
    		 PK dataset
    Number of subjects analysed
    11
    Units: pg/mL
    arithmetic mean (standard deviation)
        Age group 1
    22.9 ( 7.3 )
        Age group 2
    39.0 ( 20.4 )
        Age group 3
    72.0 ( 53.2 )
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameter tlast

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    End point title
    		 Pharmacokinetic parameter tlast [3]
    End point description
    End point type
    Primary
    End point timeframe
    Tafluprost acid concentrations were measured at the end of tafluprost dosing period.
    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: The PK of tafluprost acid was characterized by pediatric age group. Thus, no formal hypotheses were set for the study. PK variables were summarized by age group.
    End point values
    		 PK dataset
    Number of subjects analysed
    11
    Units: minute
    arithmetic mean (standard deviation)
        Age group 1
    23.3 ( 11.5 )
        Age group 2
    16.7 ( 11.5 )
        Age group 3
    34.0 ( 25.1 )
    No statistical analyses for this end point

    Primary: Pharmacokinetic parameter AUC 0-last

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    End point title
    		 Pharmacokinetic parameter AUC 0-last [4]
    End point description
    End point type
    Primary
    End point timeframe
    Tafluprost acid concentrations were measured at the end of tafluprost dosing period.
    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: The PK of tafluprost acid was characterized by pediatric age group. Thus, no formal hypotheses were set for the study. PK variables were summarized by age group.
    End point values
    		 PK dataset
    Number of subjects analysed
    11
    Units: pg/mL*min
    arithmetic mean (standard deviation)
        Age group 1
    383.4 ( 267.4 )
        Age group 2
    456.8 ( 555.3 )
        Age group 3
    1661.0 ( 1705.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All enrolled patients were included in the Safety dataset.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Enrolled
    Reporting group description
    		 -

    Serious adverse events
    		 Enrolled
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enrolled
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 18 (33.33%)
    Investigations
    IOP increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Surgical and medical procedures
    Goniotomy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Conjunctival redness
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Erythema of eyelid
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2015
    Section: 6.4.1. Inclusion criteria Old text: 1. Patient is a non-smoking male or female ≤ 17 years of age on the day of signing the informed consent with the first day of study drug dosing to occur prior to the 18th birthday. Infants must be of ≥ 36 weeks gestational age and at least 1 month of age New text: 1. Patient is a non-smoking male or female ≤ 17 years of age on the day of signing the informed consent with the first day of study drug dosing to occur prior to the 18th birthday. Infants less than 12 months old must be of ≥ 36 weeks gestational age and at least 1 month of age

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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