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    Clinical Trial Results:
    A multi-centre randomised placebo-controlled trial of prophylactic enteral lactoferrin supplementation to prevent late-onset invasive infection in very preterm infants.

    Summary
    EudraCT number
    		 2012-004260-22
    Trial protocol
    		 GB  
    Global end of trial date
    03 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Aug 2018
    First version publication date
    26 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ELFIN01
    Additional study identifiers
    ISRCTN number
    		 ISRCTN88261002
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Wellington Square, Oxford, United Kingdom,
    Public contact
    Ursula Bowler, National Perinatal Epidemiology Unit, 0044 01865289749, ursula.bowler@npeu.ox.ac.uk
    Scientific contact
    Ursula Bowler, National Perinatal Epidemiology Unit, 0044 01865289749, ursula.bowler@npeu.ox.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
    03 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the efficacy of the enteral administration of 150 mg/kg/day of bovine lactoferrin in reducing the incidence of microbiologically-confirmed or clinically suspected late-onset invasive infection (defined as more than 72 hours after birth) from trial entry until hospital discharge in a population of very preterm infants.
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2013
    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
    United Kingdom: 2203
    Worldwide total number of subjects
    2203
    EEA total number of subjects
    2203
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    2203
    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
    		 The trial was conducted in 37 neonatal units in the UK between 7th May 2014 and 28th September 2017.

    Pre-assignment
    Screening details
    		 Eligible participants were very preterm infants (gestational age at birth <32 weeks) who were <72 hours old at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, and no realistic prospect of survival.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The lactoferrin powder had similar granularity to sucrose so that when the dry IMP was shaken within the opaque, sealed pots it was not possible to distinguish lactoferrin from sucrose by the sound generated. The opaque containers did not allow the dry IMP to be seen unless the sealed stopper was removed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lactoferrin
    Arm description
    		 Bovine lactoferrin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bovine lactoferrin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Nasogastric use
    Dosage and administration details
    The IMP was prescribed at a dose of 150 mg/kg body weight per day (up to a maximum of 300 mg/day). The IMP was prepared for administration by addition by syringe of sterile water (4 mL) plus expressed breast or formula (1 mL). The pot was shaken vigorously by hand for 30 seconds to generate a mixture containing 75mg/mL of IMP. The mixture was allowed to stand for 30 minutes before removal for administration using an enteral feeding syringe. The IMP was administered once daily by naso- or oro-gastric tube once the infant’s enteral feed volume was >12 mL/kg/day and continued until 34 weeks’ postmenstrual age.

    Arm title
    		 Placebo
    Arm description
    		 Sucrose
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sucrose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Nasogastric use
    Dosage and administration details
    The IMP was prescribed at a dose of 150 mg/kg body weight per day (up to a maximum of 300 mg/day). The IMP was prepared for administration by addition by syringe of sterile water (4 mL) plus expressed breast or formula (1 mL). The pot was shaken vigorously by hand for 30 seconds to generate a mixture containing 75mg/mL of IMP. The mixture was allowed to stand for 30 minutes before removal for administration using an enteral feeding syringe. The IMP was administered once daily by naso- or oro-gastric tube once the infant’s enteral feed volume was >12 mL/kg/day and continued until 34 weeks’ postmenstrual age.

    Number of subjects in period 1
    		Lactoferrin Placebo
    Started
    1099
    1104
    Completed
    1098
    1101
    Not completed
    1
    3
         Consent withdrawn by subject
    -
    3
         Consent not confirmed
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lactoferrin
    Reporting group description
    		 Bovine lactoferrin

    Reporting group title
    Placebo
    Reporting group description
    		 Sucrose

    Reporting group values
    		 Lactoferrin Placebo Total
    Number of subjects
    		 1099 1104 2203
    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)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: days
        median (inter-quartile range (Q1-Q3))
    		 2 (2 to 3) 2 (2 to 3) -
    Gender categorical
    Units: Subjects
        Female
    		 523 521 1044
        Male
    		 575 578 1153
        Not recorded
    		 1 5 6
    Multiple pregnancy
    Units: Subjects
        Yes
    		 350 346 696
        No
    		 748 755 1503
        Not recorded
    		 1 3 4
    Caesarean section delivery
    Units: Subjects
        Yes
    		 635 616 1251
        No
    		 463 485 948
        Not recorded
    		 1 3 4
    Membranes ruptured before labour
    Units: Subjects
        Yes
    		 422 428 850
        No
    		 671 669 1340
        Not recorded
    		 6 7 13
    Membranes ruptured >24hrs before delivery
    Units: Subjects
        Yes
    		 286 264 550
        No
    		 806 832 1638
        Not recorded
    		 7 8 15
    Mother received antenatal corticosteroids
    Units: Subjects
        Yes
    		 998 997 1995
        No
    		 95 102 197
        Not recorded
    		 6 5 11
    Infant heart rate >100bpm at 5 mins
    Units: Subjects
        Yes
    		 995 1010 2005
        No
    		 95 83 178
        Not recorded
    		 9 11 20
    Infant ventilated via endotracheal tube at randomisation
    Units: Subjects
        Yes
    		 338 357 695
        No
    		 760 744 1504
        Not Recorded
    		 1 3 4
    Infant had absent or reverse end diastolic flow
    Units: Subjects
        Yes
    		 134 130 264
        No
    		 945 951 1896
        Not recorded
    		 20 23 43
    Birth weight
    Units: grams
        arithmetic mean (standard deviation)
    		 1126 ( 356 ) 1143 ( 367 ) -
    Completed weeks gestation at delivery
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    		 29 (27 to 30) 29 (27 to 30) -
    Mother's age at trial entry
    Units: years
        arithmetic mean (standard deviation)
    		 30.3 ( 6.1 ) 30.4 ( 6.0 ) -
    Infant temperature on admission
    Units: degrees centigrade
        arithmetic mean (standard deviation)
    		 36.9 ( 0.7 ) 37 ( 0.7 ) -
    Infant worst base excess within first 24 hours of birth
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 -6.2 ( 3.9 ) -6.3 ( 3.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    Lactoferrin
    Reporting group description
    		 Bovine lactoferrin

    Reporting group title
    Placebo
    Reporting group description
    		 Sucrose

    Primary: Microbiologically-confirmed or clinically suspected late-onset infection

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    End point title
    		 Microbiologically-confirmed or clinically suspected late-onset infection
    End point description
    End point type
    Primary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1093
    1089
    Units: Number of infants
        Yes
    316
    334
        No
    777
    755
    Statistical analysis title
    		 Adjusted risk ratio
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.233
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.95
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.04

    Secondary: Microbiologically-confirmed late-onset infection

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    End point title
    		 Microbiologically-confirmed late-onset infection
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1093
    1089
    Units: Number of infants
        Yes
    190
    180
        No
    903
    909
    Statistical analysis title
    		 Adjusted risk ratio
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.49
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.05
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.26

    Secondary: All-cause mortality

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    End point title
    		 All-cause mortality
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1076
    1076
    Units: Number of infants
        Yes
    71
    68
        No
    1005
    1008
    Statistical analysis title
    		 Adjusted risk ratio
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.782
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.05
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.68

    Secondary: Necrotising enterocolitis Bell stage II and above

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    End point title
    		 Necrotising enterocolitis Bell stage II and above
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1085
    1084
    Units: Number of infants
        Yes
    63
    56
        No
    1022
    1028
    Statistical analysis title
    		 Adjusted risk ratio
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.538
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.13
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.89

    Secondary: Severe retinopathy of prematurity treated medically or surgically

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    End point title
    		 Severe retinopathy of prematurity treated medically or surgically
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1080
    1080
    Units: Number of infants
        Yes
    64
    72
        No
    1016
    1008
    Statistical analysis title
    		 Adjusted risk ratio
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.89
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.28

    Secondary: Bronchopulmonary dysplasia at 36 week postmentrual age

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    End point title
    		 Bronchopulmonary dysplasia at 36 week postmentrual age
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1023
    1027
    Units: Number of infants
        Yes
    358
    355
        No
    665
    672
    Statistical analysis title
    		 Adjusted risk ratio
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2050
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.867
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.13

    Secondary: Late-onset infection, NEC, ROP, BPD or mortality

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    End point title
    		 Late-onset infection, NEC, ROP, BPD or mortality
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1092
    1094
    Units: Number of infants
        Yes
    525
    521
        No
    567
    573
    Statistical analysis title
    		 Adjusted risk ratio
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.743
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.08

    Secondary: Administration of antimicrobials

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    End point title
    		 Administration of antimicrobials
    End point description
    End point type
    Secondary
    End point timeframe
    From commencment of IMP until 34 weeks postmenstrual age
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1059
    1057
    Units: days
        median (inter-quartile range (Q1-Q3))
    2 (0 to 8)
    3 (0 to 8)
    Statistical analysis title
    		 Median difference
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.625
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1

    Secondary: Length of hospital stay

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    End point title
    		 Length of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1003
    1004
    Units: days
        median (inter-quartile range (Q1-Q3))
    59 (40 to 85)
    58 (40 to 84)
    Statistical analysis title
    		 Median difference
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2007
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.446
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 3

    Secondary: Length of stay in intensive care

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    End point title
    		 Length of stay in intensive care
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1011
    1035
    Units: days
        median (inter-quartile range (Q1-Q3))
    8 (4 to 16)
    8 (4 to 16)
    Statistical analysis title
    		 Median difference
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2046
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.963
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1

    Secondary: Length of stay in high dependency care

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    End point title
    		 Length of stay in high dependency care
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1015
    1041
    Units: days
        median (inter-quartile range (Q1-Q3))
    10 (3 to 30)
    9 (3 to 29)
    Statistical analysis title
    		 Median difference
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2056
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 3

    Secondary: Length of stay in special care

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    End point title
    		 Length of stay in special care
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to hospital discharge home
    End point values
    		 Lactoferrin Placebo
    Number of subjects analysed
    1023
    1046
    Units: days
        median (inter-quartile range (Q1-Q3))
    29 (21 to 39)
    30 (22 to 39)
    Statistical analysis title
    		 Median difference
    Comparison groups
    Lactoferrin v Placebo
    Number of subjects included in analysis
    2069
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.216
    Method
    		 Quantile regression
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 1

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From trial entry to hospital discharge home
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    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: Not collected as there are multiple non-serious adverse events in this population of very preterm babies.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2013
    Text amendments to protocol. IMP Dossier amended. Consent form amended. Parent information leaflet amended. ELFIN Statement of Responsibilities introduced.
    17 Jan 2014
    IMP Dossier amended.
    27 May 2014
    ELFIN/SIFT Summary Leaflet added.
    21 Jul 2014
    Notification of temporary halt to trial.
    29 Oct 2014
    Two parent posters introduced.
    03 Nov 2014
    IMP Dossier amended. Storage requirements of IMP changed.
    23 Apr 2015
    Addition of extra recruiting sites in England.
    31 Jul 2015
    Parent information leaflet and consent form amended.
    10 Sep 2015
    Some continuing care sites converted to recruiting sites.
    16 Dec 2015
    Removed requirement for temperature monitoring of IMP at continuing care sites.
    31 Dec 2015
    Amendment to text in protocol.
    21 Jan 2016
    Conversion of additional continuing care sites to recruiting sites.
    04 Mar 2016
    Amendments to text in protocol.
    09 Aug 2016
    Additional recruiting sites and change in PIs at existing sites.
    21 Nov 2016
    Added continuing care sites in Wales and adapted PIL for Wales.
    06 Sep 2017
    Change of existing PI at a a site.
    15 Mar 2018
    Amendment to text in protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    21 Jul 2014
    Temporary halt to trial recruitment due to IMP issues.
    03 Nov 2014

    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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    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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