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    Clinical Trial Results:
    Melatonin As A Novel Neuroprotectant in Preterm Infants- Dosage study

    Summary
    EudraCT number
    		 2007-007156-33
    Trial protocol
    		 GB  
    Global end of trial date
    22 Feb 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2020
    First version publication date
    06 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO970 (MIND)
    Additional study identifiers
    ISRCTN number
    		 ISRCTN01115788
    US NCT number
    		 NCT00649961
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensington Campus, London, United Kingdom, SW7 2AZ
    Public contact
    Dr Nazakat Merchant, Imperial College London, +44 07825881907, nazakat.merchant@kcl.ac.uk
    Scientific contact
    Dr Nazakat Merchant, Imperial College London, +44 07825881907, nazakat.merchant@kcl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Feb 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Feb 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall purpose is to investigate whether melatonin, on achieving adult maternal peak blood levels in preterm infants, will reduce cerebral white matter disease as defined by specialised magnetic resonance imaging (MRI) at term. Before testing this hypothesis in a clinical trial, the dose of melatonin required to achieve the desired concentration in preterm infants needs to be determined. This data will be used in the clinical double blinded randomised trial for which a separate application will be made to the ethics committee. The principal research objective in this study is to determine the dose required to achieve physiological melatonin blood levels in the preterm infants similar to that of the mother.
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 May 2010
    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: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    18
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    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
    		 The investigators conducted an open-label dose-ranging study between May 2010 and December 2010 in three neonatal intensive care units in the UK. Infants born less than 31 weeks gestation and less than 7 days old were eligible for the study.

    Pre-assignment
    Screening details
    		 Eighteen preterm infants (nine male, nine female) born before 31 weeks gestation and less than 7 days of postnatal age were enrolled into the study.

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

    Arms
    Arm title
    		 Melatonin Open Label Single Arm - all participants
    Arm description
    		 A single intravenous infusion of melatonin was given to each infant over 6 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melatonin injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravesical use
    Dosage and administration details
    The first dose administered was 0.1 mg kg-1 h-1 for 6 h. Successive groups received varying doses depending on the melatonin blood concentrations until mean adult physiological concentrations were achieved (approximately 46–58 pg ml-1). The dose regimens given were 0.1 mg kg-1 h-1 intravenously for 6 h, 0.1 mg kg-1 h-1 for 2 h, 0.02 mg kg-1 h-1 for 2 h, 0.01 mg kg-1 h-1 for 2 h and 0.04 mg kg-1 over 30 min.

    Number of subjects in period 1
    		Melatonin Open Label Single Arm - all participants
    Started
    18
    Completed
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Reporting group values
    		 Overall Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
        Newborns (0-27 days)
    		 18 18
    Age continuous
    Gestation at birth
    Units: weeks
        arithmetic mean (full range (min-max))
    		 26.63 (24.71 to 30.28) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 9 9
    Postnatal age
    Units: day
        arithmetic mean (full range (min-max))
    		 2 (1 to 6) -
    Birth weight
    Units: gram(s)
        arithmetic mean (full range (min-max))
    		 867.5 (610 to 1430) -

    End points

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    End points reporting groups
    Reporting group title
    Melatonin Open Label Single Arm - all participants
    Reporting group description
    		 A single intravenous infusion of melatonin was given to each infant over 6 hours.

    Subject analysis set title
    0.1 mg kg-1 h-1 for 2 h
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    0.1 mg kg-1 h-1 for 6 h

    Subject analysis set title
    0.02 mg kg-1 h-1 for 2 h
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    0.02 mg kg-1 h-1 for 2 h

    Subject analysis set title
    0.01 mg kg-1 h-1 for 2 h
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    0.01 mg kg-1 h-1 for 2 h

    Primary: Dose of Melatonin Required to Achieve Physiological Blood Levels in the Preterm Infants Similar to That of the Mother

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    End point title
    		 Dose of Melatonin Required to Achieve Physiological Blood Levels in the Preterm Infants Similar to That of the Mother [1]
    End point description
    Blood results at 2h, a dose of melatonin required to achieve physiological blood levels in the preterm infants similar to that of the mother is 160-220 pg/ml
    End point type
    Primary
    End point timeframe
    6 months
    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: This is a pharmacokinetic study with a mathematical basis and that the reporting format doesn’t lend itself to this type of study.
    End point values
    		 0.1 mg kg-1 h-1 for 2 h 0.02 mg kg-1 h-1 for 2 h 0.01 mg kg-1 h-1 for 2 h
    Number of subjects analysed
    4
    6
    2
    Units: pg/ml
        median (full range (min-max))
    203.3 (160 to 220)
    48.7 (38.8 to 71)
    54.8 (43.5 to 66)
    No statistical analyses for this end point

    Secondary: The Pharmacokinetic Profile of Melatonin in Preterm Infants - Percent of the Clearance (CL)

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    End point title
    		 The Pharmacokinetic Profile of Melatonin in Preterm Infants - Percent of the Clearance (CL)
    End point description
    The Melatonin clearance (l h-1/0.867 kg) in Preterm Infants
    End point type
    Secondary
    End point timeframe
    6 hours
    End point values
    		 0.1 mg kg-1 h-1 for 2 h 0.02 mg kg-1 h-1 for 2 h 0.01 mg kg-1 h-1 for 2 h
    Number of subjects analysed
    8
    8
    8
    Units: percent
    8
    15
    15
    No statistical analyses for this end point

    Secondary: he Pharmacokinetic Profile of Melatonin in Preterm Infants - Percent of the Volume of Distribution (V)

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    End point title
    		 he Pharmacokinetic Profile of Melatonin in Preterm Infants - Percent of the Volume of Distribution (V)
    End point description
    The volume of distribution (l/0.867 kg)
    End point type
    Secondary
    End point timeframe
    6 hours
    End point values
    		 0.1 mg kg-1 h-1 for 2 h 0.02 mg kg-1 h-1 for 2 h 0.01 mg kg-1 h-1 for 2 h
    Number of subjects analysed
    8
    8
    8
    Units: percent
    11
    32
    32
    No statistical analyses for this end point

    Secondary: The Pharmacokinetic Profile of Melatonin in Preterm Infants - Percent of the Residual Variability

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    End point title
    		 The Pharmacokinetic Profile of Melatonin in Preterm Infants - Percent of the Residual Variability
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours
    End point values
    		 0.1 mg kg-1 h-1 for 2 h 0.02 mg kg-1 h-1 for 2 h 0.01 mg kg-1 h-1 for 2 h
    Number of subjects analysed
    8
    8
    8
    Units: percent
    30
    63
    63
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    6 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Melatonin Open Label Single Arm - all participants
    Reporting group description
    		 A single intravenous infusion of melatonin was given to each infant over 6 hours.

    Serious adverse events
    		 Melatonin Open Label Single Arm - all participants
    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: 0%
    Non-serious adverse events
    		 Melatonin Open Label Single Arm - all participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse events reported.

    More information

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

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23432339
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    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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