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    Clinical Trial Results:
    NIRTURE - A Randomised Trial of Early Insulin Therapy in Very Low Birth Weight Infants

    Summary
    EudraCT number
    		 2004-002170-34
    Trial protocol
    		 ES  
    Global end of trial date
    15 Feb 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jul 2016
    First version publication date
    31 Jul 2015
    Other versions
    Summary report(s)
    		 SAE and AE Listing

    Trial information

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    Trial identification
    Sponsor protocol code
    15/1/04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cambridge Univeristy Hospitals NHS foundation Trust
    Sponsor organisation address
    R&D office Box 146, Addenbrookes NHS Trust, Cambridge, United Kingdom, CB0 0QQ
    Public contact
    Diane Picton , Cambridge University Hospitals NHS Foundation Trust , 44 1223762944, dp223@medschl.cam.ac.uk
    Scientific contact
    Dr Kathy Bearsdall , Cambridge University Hospitals NHS Foundation Trust , 44 1223746791, kb274@medschl.cam.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
    30 Oct 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Nov 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of early fixed dose insulin on mortality in very low birth weight babies
    Protection of trial subjects
    Regular reporting of SAE’s and meetings held yearly
    Background therapy
    		 Insulin aspart with variable rate 20% dextrose support, Dose 0.05 units/kg/hour, Route of administration Continuous intravenous infusion in the first week of life
    Evidence for comparator
    		 Standard care
    Actual start date of recruitment
    04 Feb 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    United Kingdom: 108
    Country: Number of subjects enrolled
    Belgium: 211
    Country: Number of subjects enrolled
    Netherlands: 45
    Worldwide total number of subjects
    389
    EEA total number of subjects
    389
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    389
    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)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Very low birth weight infants (<1500g) were recruited from neonatal intensive care units and randomised to receive either a continuous infusion of insulin (0.05 u/kg/hr) from within 24 hours of birth and for the first 7 days of life, or to act as controls and receive standard neonatal care. Recuitment opened in Feb 2005 & closed June/July 2007.

    Pre-assignment
    Screening details
    		 Screening for eligibility was performed in conjunction with the clinical team

    Period 1
    Period 1 title
    Start-end of study intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 Early fixed dose insulin replacement
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Aspart
    Investigational medicinal product code
    Other name
    Novorapid
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.05u/kg/hr

    Arm title
    		 Control
    Arm description
    		 Standard care
    Arm type
    		 Standard Care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Intervention Control
    Started
    195
    194
    Completed
    194
    192
    Not completed
    1
    2
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Early fixed dose insulin replacement

    Reporting group title
    Control
    Reporting group description
    		 Standard care

    Reporting group values
    		 Intervention Control Total
    Number of subjects
    		 195 194 389
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 194 192 386
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Not recorded
    		 1 2 3
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    		 27.6 ( 2.2 ) 27.8 ( 2.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 101 95 196
        Male
    		 94 99 193
    Receipt of Antenatal glucocorticoids
    Units: Subjects
        yes
    		 178 176 354
        no
    		 16 16 32
        not recorded
    		 1 2 3
    Birth Weight
    Birth Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 1.007 ( 0.267 ) 1.009 ( 0.274 ) -
    Head Circumference
    Units: cm
        arithmetic mean (standard deviation)
    		 25.3 ( 2.2 ) 25.4 ( 2.3 ) -
    Crown Heel Length
    Units: cm
        arithmetic mean (standard deviation)
    		 35.3 ( 3.7 ) 35.4 ( 3.6 ) -
    Birth Weight SDS
    Units: SDS
        arithmetic mean (standard deviation)
    		 -0.84 ( 1.1 ) -0.91 ( 1.1 ) -
    CRIB score
    Units: number
        arithmetic mean (standard deviation)
    		 3.99 ( 3.5 ) 4.02 ( 3.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Early fixed dose insulin replacement

    Reporting group title
    Control
    Reporting group description
    		 Standard care

    Primary: Death on or before expected date of delivery (taken as date considered to be the most accurate estimate of delivery date).

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    End point title
    		 Death on or before expected date of delivery (taken as date considered to be the most accurate estimate of delivery date).
    End point description
    End point type
    Primary
    End point timeframe
    Death on or before expected date of delivery (taken as date considered to be the most accurate estimate of delivery date).
    End point values
    		 Intervention Control
    Number of subjects analysed
    195
    194
    Units: subjects
        Death before expected date of delivery
    28
    18
        Alive at expected date of delivery
    166
    174
        Not Recorded
    1
    2
    Statistical analysis title
    		 Death before expected delivery date
    Statistical analysis description
    Fisher's exact test applied to the frequency table cross-classifying the binary endpoint (death before expected deliver date) against treatment arm
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.15

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    24 hours
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Protocol Based
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0%
    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: A listing of serious adverse events are given in an attachment

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Oct 2004
    Protocol changes post original submission
    25 Nov 2004
    Change in Trial stastistician ,Secondary Endpoints and randomsiation procedure.
    17 Jun 2005
    Change of Trial Statistician and DMC Statistician to ensure independence. Revised study documentation
    11 Jan 2006
    Justification to allow recruitment to multiple trial
    19 Apr 2006
    Follow up plans - Appendix 3 (follow-up protocol). Patient information sheets and consent forms V2 ( April 2006)
    25 Jun 2006
    Change of PI
    03 Apr 2007
    Plans to follow-up participants through Office of National Stastistic (ONS)
    15 Aug 2007
    Recruitment suspended
    13 Sep 2007
    Recruitment stopped on ground of futility
    20 Jun 2008
    Specifically requesting cause of death
    06 Sep 2009
    Change of Sponsor. Sent in for notification only but reviewed formally by ethic committee

    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/18971490
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