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    Clinical Trial Results:
    A randomised controlled trial of iodide supplementation in preterm infants with follow-up at 2 years

    Summary
    EudraCT number
    2008-001024-31
    Trial protocol
    GB  
    Global end of trial date
    22 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Apr 2016
    First version publication date
    28 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    08/S0501/31
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00638092
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    CTRG, Joint Research Office, Block 60, Churchill Hospital, Old Road, Headington,, Oxford , United Kingdom, OX3 7LE
    Public contact
    Fiona Williams, Population Health Sciences, Medical Research Institute, University of Dundee, DD2 4B, Fiona Williams, Population Health Sciences, Medical Research Institute, University of Dundee, DD2 4B, 01382 383726, f.l.r.williams@dundee.ac.uk
    Scientific contact
    Fiona Williams, Population Health Sciences, Medical Research Institute, University of Dundee, DD2 4B, Fiona Williams, Population Health Sciences, Medical Research Institute, University of Dundee, DD2 4B, 01382 383726, f.l.r.williams@dundee.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
    27 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does iodide supplementation of extreme preterm infants improve neurodevelopmental outcome at 2 years corrected age?
    Protection of trial subjects
    The trial solutions were given as part of routine nutrition - no pain or inconvenience was associated. Blood for trial measurements was coincided with routine clinical blood samples - so no additional pain or inconvenience was associated with trial participation.
    Background therapy
    All infants in I2S2 trial were recruited while in neonatal intensive care units and they remained in the units for the duration of the intervention phase of the trial. As such all infants were very likely in receipt of a range of drug and clinical therapies.
    Evidence for comparator
    The comparator was sodium chloride at chloride content of 75mcg/ml. The daily chloride allowance for preterm neonates is 2 mmol/kg/day and the additional chloride content derived from the trial solutions was miniscule. The placebo was given in the same dose and volume as the intervention and the solutions were visually indistinguishable.
    Actual start date of recruitment
    10 Mar 2010
    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: 1259
    Worldwide total number of subjects
    1259
    EEA total number of subjects
    1259
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    1259
    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
    Infants were eligible if they were <42 hours old, born <31 weeks' gestation in one of the 21 trial recruiting hospitals and had a realistic prospect of survival.

    Pre-assignment
    Screening details
    The only exclusion criterion was maternal exposure to iodine during pregnancy or delivery.

    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
    Investigator, Monitor, Data analyst, Carer, Subject, Assessor
    Blinding implementation details
    The packaging and visual appearance of trial solutions was identical; the dose for both was 30 mcg/kg/day, given daily from randomisation until the equivalent of 34 weeks' gestational age (had the fetus remained in utero), referred to hereafter as equivalent gestational age. The trial solutions could be given parenterally or enterally. Masking ensured that the research team, parents of I2S2 participants, neonatal staff and pharmacy were blind to the content of the trial solutions.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sodium Chloride
    Arm description
    This is the placebo arm
    Arm type
    Placebo

    Investigational medicinal product name
    Sodium Chloride
    Investigational medicinal product code
    sodium chloride
    Other name
    NaCl
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Enteral use , Parenteral use
    Dosage and administration details
    30 mcg/kg/day. Enteral or parenteral use.

    Arm title
    Sodium Iodide
    Arm description
    This is the intervention arm
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium Iodide
    Investigational medicinal product code
    Other name
    sodium iodide injection BP 2004
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Enteral use , Parenteral use
    Dosage and administration details
    30 mcg/kg/day Enteral or parenteral route

    Number of subjects in period 1
    Sodium Chloride Sodium Iodide
    Started
    628
    631
    Completed
    628
    631

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sodium Chloride
    Reporting group description
    This is the placebo arm

    Reporting group title
    Sodium Iodide
    Reporting group description
    This is the intervention arm

    Reporting group values
    Sodium Chloride Sodium Iodide Total
    Number of subjects
    628 631 1259
    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
    gestational age at birth
    Units: weeks
        arithmetic mean (standard deviation)
    27.4 ± 2 27.4 ± 2 -
    Gender categorical
    Units: Subjects
        Female
    281 282 563
        Male
    347 349 696
    Main causes of preterm birth
    Main causes of preterm birth
    Units: Subjects
        pre-labour rupture of membranes
    183 173 356
        preterm labour without PROM
    201 215 416
        Antepartum haemorrhage
    60 66 126
        Pregnancy induced hypertension with or without APH
    68 54 122
        Other maternal illness
    58 55 113
        Poor fetal growth
    56 67 123
        Other
    2 1 3
        missing data
    0 0 0
    Infant ancestry
    Units: Subjects
        Black
    23 16 39
        Asian
    43 48 91
        White
    516 531 1047
        Other
    45 35 80
        missing data
    1 1 2
    Region of birth
    Units: Subjects
        Scotland
    135 140 275
        North East England
    183 183 366
        remainder England
    264 263 527
        Northern Ireland
    46 45 91
    Analgesia given during labour
    Units: Subjects
        none
    52 54 106
        entonox
    136 132 268
        general anaesthesia
    62 70 132
        epidural/spinal
    205 219 424
        opiod
    20 15 35
        other
    10 8 18
        More than one form of pain relief given
    132 125 257
        missing data
    11 8 19
    Smoking status (maternal)
    Units: Subjects
        current
    139 150 289
        ex
    86 68 154
        non
    401 410 811
        missing data
    2 3 5
    maternal steroids given (other than for RDS)
    RDS= respiratory distress syndrome
    Units: Subjects
        yes
    34 40 74
        no
    594 591 1185
    maternal steroids given for prevention of RDS
    RDS= Respiratory distress syndrome
    Units: Subjects
        yes
    569 586 1155
        no
    59 45 104
    maternal thyroid disease
    concurrent with pregnancy
    Units: Subjects
        yes
    19 22 41
        no
    609 609 1218
    Mode of delivery
    Units: Subjects
        spontaneous cephalic vaginal
    237 221 458
        vaginal breech
    69 74 143
        instrumental cephalic vaginal
    14 11 25
        elective caesarean
    33 41 74
        emergency caesarean
    275 284 559
    Agar Score at 5 mins
    Apgar Score at 5 minutes of age
    Units: Apgar points
        arithmetic mean (standard deviation)
    7.8 ± 1.8 7.8 ± 1.8 -
    Age at receipt of first trial solution
    Age at receipt of first trial solution
    Units: hr:min
        arithmetic mean (standard deviation)
    39.03 ± 13.77 39.3 ± 15.15 -
    Birth weight
    Units: grams
        arithmetic mean (standard deviation)
    1053 ± 309 1055 ± 308 -
    maternal age at delivery
    Units: years
        arithmetic mean (standard deviation)
    29.4 ± 6.5 29.3 ± 6.4 -

    End points

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    End points reporting groups
    Reporting group title
    Sodium Chloride
    Reporting group description
    This is the placebo arm

    Reporting group title
    Sodium Iodide
    Reporting group description
    This is the intervention arm

    Primary: Bayley-III Cognitive Score

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    End point title
    Bayley-III Cognitive Score
    End point description
    Cognitive score is a Bayley-III main domain. The data included in this table are the intention-to-treat population and includes deaths and severely disabled infants who were coded 55; missing outcomes for losses to follow up were imputed using multiple imputation.
    End point type
    Primary
    End point timeframe
    Bayley-III neurodevelopment assessment was measured in all infants at 2 years of age corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: Bayley units
        arithmetic mean (standard deviation)
    89.2 ± 19.5
    88.9 ± 19.2
    Statistical analysis title
    95% CI
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (net)
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.57
         upper limit
    1.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.136

    Primary: Bayley-III Motor Composite Score

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    End point title
    Bayley-III Motor Composite Score
    End point description
    The Bayley-III motor composite scale is a main domain of the Bayley-III The data included in this table are the intention-to-treat population and includes deaths and severely disabled infants who were coded 46; missing outcomes for losses to follow up were imputed using multiple imputation.
    End point type
    Primary
    End point timeframe
    2 years corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: Bayley units
        arithmetic mean (standard deviation)
    88 ± 21.6
    88.2 ± 21
    Statistical analysis title
    95% Confidence Interval
    Statistical analysis description
    Comparison was sodium iodide v sodium chloride
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (net)
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.23
         upper limit
    2.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.243

    Primary: Bayley-III Language composite score

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    End point title
    Bayley-III Language composite score
    End point description
    The Bayley-III language composite scale is a main domain of the Bayley-III The data included in this table are the intention-to-treat population and includes deaths and severely disabled infants who were coded 47; missing outcomes for losses to follow up were imputed using multiple imputation.
    End point type
    Primary
    End point timeframe
    at two years of age corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: Bayley-III units
        arithmetic mean (standard deviation)
    85.2 ± 21.8
    85.1 ± 21.7
    Statistical analysis title
    95% CI
    Statistical analysis description
    95% Confidence Interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (net)
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.48
         upper limit
    2.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.24

    Primary: Bayley-III cognitive score (including death and severe disability)

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    End point title
    Bayley-III cognitive score (including death and severe disability)
    End point description
    Single imputation was used for deaths and severe disability, which were coded 55 (These data exclude infants lost to follow up)
    End point type
    Primary
    End point timeframe
    2 years corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    576
    572
    Units: bayley
        arithmetic mean (standard deviation)
    88.7 ± 19.8
    88.2 ± 19.4
    Statistical analysis title
    95% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1148
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (net)
    Point estimate
    -0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.69
         upper limit
    1.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.16

    Primary: Bayley-III motor composite score (including death and severe disability)

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    End point title
    Bayley-III motor composite score (including death and severe disability)
    End point description
    Single imputation was used for deaths and severe disability, which were coded 46 (These data exclude infants lost to follow up)
    End point type
    Primary
    End point timeframe
    measured at 2 years corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    576
    571
    Units: Bayley units
        arithmetic mean (standard deviation)
    87.5 ± 22
    87.6 ± 21.4
    Statistical analysis title
    95% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (net)
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.44
         upper limit
    2.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.28

    Primary: Bayley-III Language composite score (including death and severe disability)

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    End point title
    Bayley-III Language composite score (including death and severe disability)
    End point description
    Single imputation was used for deaths and severe disability, which were coded 47 (These data exclude infants lost to follow up)
    End point type
    Primary
    End point timeframe
    measured at 2 years of age corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    574
    572
    Units: Bayley-III units
        arithmetic mean (standard deviation)
    84.7 ± 22.1
    84.6 ± 22
    Statistical analysis title
    95% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (net)
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.71
         upper limit
    2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.3

    Secondary: Bayley-III Subset score: Receptive Language

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    End point title
    Bayley-III Subset score: Receptive Language
    End point description
    The data included in this table are the intention-to-treat population and includes deaths and severely disabled who were coded at the lowest achievable score; missing outcomes for losses were imputed using multiple imputation
    End point type
    Secondary
    End point timeframe
    measured at two years of age, corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: Bayley units
        arithmetic mean (standard deviation)
    7.46 ± 3.77
    7.51 ± 3.8
    Statistical analysis title
    99% Confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    0.05
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    0.61

    Secondary: Bayley-III Subset score: Expressive Language

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    End point title
    Bayley-III Subset score: Expressive Language
    End point description
    The data included in this table are the intention-to-treat population and includes deaths and severely disabled who were coded at the lowest achievable score; missing outcomes for losses were imputed using multiple imputation
    End point type
    Secondary
    End point timeframe
    measured at 2 years of age corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: Bayley units
        arithmetic mean (standard deviation)
    7.34 ± 4.06
    7.31 ± 4.06
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    0.57

    Secondary: Bayley-III Subset score: Fine Motor

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    End point title
    Bayley-III Subset score: Fine Motor
    End point description
    The data included in this table are the intention-to-treat population and includes deaths and severely disabled who were coded at the lowest achievable score; missing outcomes for losses were imputed using multiple imputation
    End point type
    Secondary
    End point timeframe
    measured at 2 years of age corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: Bayley units
        arithmetic mean (standard deviation)
    8.72 ± 4.13
    8.86 ± 3.99
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    0.15
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -0.47
         upper limit
    0.76

    Secondary: Bayley-III subset score: Gross Motor

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    End point title
    Bayley-III subset score: Gross Motor
    End point description
    The data included in this table are the intention-to-treat population and includes deaths and severely disabled who were coded at the lowest achievable score; missing outcomes for losses were imputed using multiple imputation
    End point type
    Secondary
    End point timeframe
    Measured at 2 years corrected for prematurity
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: Bayley units
        arithmetic mean (standard deviation)
    7.16 ± 3.68
    7.07 ± 3.61
    Statistical analysis title
    99% confidnece intervals
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    -0.09
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -0.63
         upper limit
    0.45

    Secondary: Composite outcome

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    End point title
    Composite outcome
    End point description
    Low Bayley-III score (or death) in any of the main Bayley-III domains (i.e. cognitive, motor composite or language composite) in the intention-to-treat population
    End point type
    Secondary
    End point timeframe
    counted at two years of age
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        Bayley-III equal to or over 85
    320
    306
        Bayley-III under 85 (or death)
    308
    325
    Statistical analysis title
    Odds Ratio
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.49

    Secondary: postnatal conditions-chronic lung disease

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    End point title
    postnatal conditions-chronic lung disease
    End point description
    End point type
    Secondary
    End point timeframe
    counted at the equivalent of 36 week's gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    235
    262
        no
    393
    367
        missing data
    0
    2
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.19
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.61

    Secondary: Postnatal conditions- respiratory distress syndrome

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    End point title
    Postnatal conditions- respiratory distress syndrome
    End point description
    End point type
    Secondary
    End point timeframe
    counted at the equivalent of 36 week's gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    581
    591
        no
    47
    38
        data missing
    0
    2
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.26
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    2.25

    Secondary: Postnatal conditions - persistent ductus arteriosus

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    End point title
    Postnatal conditions - persistent ductus arteriosus
    End point description
    End point type
    Secondary
    End point timeframe
    counted at the equivalent of 36 week's gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    195
    192
        no
    433
    437
        data missing
    0
    2
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.34

    Secondary: Postnatal conditions - necrotising enterocolitis

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    End point title
    Postnatal conditions - necrotising enterocolitis
    End point description
    End point type
    Secondary
    End point timeframe
    counted at the equivalent of 36 week's gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    103
    128
        no
    525
    501
        missing data
    0
    2
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.9

    Secondary: Postnatal illnesses - hyperbilirubinaemia

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    End point title
    Postnatal illnesses - hyperbilirubinaemia
    End point description
    End point type
    Secondary
    End point timeframe
    collected at the equivalent of 36 week's gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    519
    522
        no
    109
    107
        missing data
    0
    2
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.51

    Secondary: Postnatal conditions - infants with more than one acquired infection

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    End point title
    Postnatal conditions - infants with more than one acquired infection
    End point description
    End point type
    Secondary
    End point timeframe
    collected at the equivalent of 36 week's gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    258
    283
        no
    370
    346
        missing data
    0
    2
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    1.16

    Secondary: Postnatal conditions- cerebral pathology

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    End point title
    Postnatal conditions- cerebral pathology
    End point description
    End point type
    Secondary
    End point timeframe
    measured closest to the equivalent of 34 week's gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    89
    93
        no
    392
    385
        missing data
    147
    153
    Statistical analysis title
    99% confidence interval
    Statistical analysis description
    summary statistic
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.94
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    1.44

    Secondary: Hearing impairment

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    End point title
    Hearing impairment
    End point description
    Hearing impairment = deaf or requires hearing aids
    End point type
    Secondary
    End point timeframe
    counted at 2 years of age
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    14
    15
        no
    528
    536
        missing data
    86
    80
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.06
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    2.79

    Secondary: vision impairment

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    End point title
    vision impairment
    End point description
    vision impairment = blind or difficulty seeing even with glasses
    End point type
    Secondary
    End point timeframe
    counted at 2 years of age
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        yes
    14
    9
        no
    527
    542
        missing data
    87
    80
    Statistical analysis title
    99% confidence interval
    Comparison groups
    Sodium Iodide v Sodium Chloride
    Number of subjects included in analysis
    1259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    1.9

    Secondary: Level of Nursing Care Day 7

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    End point title
    Level of Nursing Care Day 7
    End point description
    End point type
    Secondary
    End point timeframe
    counted at day 7 postnatal
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        Level 1
    321
    323
        Level 2
    212
    206
        Level 3
    82
    84
        missing data
    13
    18
    No statistical analyses for this end point

    Secondary: Level of Nursing Care day 14

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    End point title
    Level of Nursing Care day 14
    End point description
    End point type
    Secondary
    End point timeframe
    day 14 postnatal
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        Level1
    219
    230
        Level 2
    230
    200
        Level 3
    147
    168
        missing data
    32
    33
    No statistical analyses for this end point

    Secondary: Level of Nursing Care day 28

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    End point title
    Level of Nursing Care day 28
    End point description
    End point type
    Secondary
    End point timeframe
    day 28 postnatal
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        Level 1
    131
    137
        Level 2
    228
    216
        Level 3
    218
    230
        missing data
    51
    48
    No statistical analyses for this end point

    Secondary: Level of Nursing Care at the equivalent of 34 weeks gestation

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    End point title
    Level of Nursing Care at the equivalent of 34 weeks gestation
    End point description
    End point type
    Secondary
    End point timeframe
    the equivalent of 34 weeks gestation
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    628
    631
    Units: infants
        Level 1
    33
    39
        Level 2
    181
    188
        Level 3
    355
    337
        missing data
    59
    67
    No statistical analyses for this end point

    Secondary: Cognitive Score by Hypothyroxinaemic status

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    End point title
    Cognitive Score by Hypothyroxinaemic status
    End point description
    Infant thyroxinaemic status was classified as hypothyroxinaemia - a T4 level at or below the 10th percentile, corrected to gestational age subgroup (i.e. ≤25, 26-27, 28-30 weeks) on postnatal days 7, 14 or 28; euthyroid constituted the remainder.
    End point type
    Secondary
    End point timeframe
    Hypothyroxinaemic status classified during first 28 days of life, neurodevelopment outcome assessed at 2 years of age
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    498
    498
    Units: Bayley-III units
    arithmetic mean (standard deviation)
        hypothyroxinaemic
    89 ± 17
    92 ± 15
        euthyroid
    95 ± 15
    94 ± 16
    No statistical analyses for this end point

    Secondary: Motor Composite Score by Hypothyroxinaemic status

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    End point title
    Motor Composite Score by Hypothyroxinaemic status
    End point description
    Infant thyroxinaemic status was classified as hypothyroxinaemia - a T4 level at or below the 10th percentile, corrected to gestational age subgroup (i.e. ≤25, 26-27, 28-30 weeks) on postnatal days 7, 14 or 28; euthyroid constituted the remainder.
    End point type
    Secondary
    End point timeframe
    Hypothyroxinaemic status classified during first 28 days of life, neurodevelopment outcome assessed at 2 years of age.
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    498
    497
    Units: Bayley-III units
    arithmetic mean (standard deviation)
        Hypothyroxinaemic
    91 ± 18
    92 ± 14
        Euthyroid
    95 ± 15
    94 ± 15
    No statistical analyses for this end point

    Secondary: Language Composite Score by Hypothyroxinaemic status

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    End point title
    Language Composite Score by Hypothyroxinaemic status
    End point description
    Infant thyroxinaemic status was classified as hypothyroxinaemia - a T4 level at or below the 10th percentile, corrected to gestational age subgroup (i.e. ≤25, 26-27, 28-30 weeks) on postnatal days 7, 14 or 28; euthyroid constituted the remainder.
    End point type
    Secondary
    End point timeframe
    Hypothyroxinaemic status classified during first 28 days of life, neurodevelopment outcome assessed at 2 years of age.
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    496
    498
    Units: Bayley-III units
    arithmetic mean (standard deviation)
        Hypothyroxinaemic
    85 ± 19
    89 ± 18
        Euthyroid
    92 ± 17
    91 ± 18
    No statistical analyses for this end point

    Secondary: Receptive language by hypothyroxinaemic status

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    End point title
    Receptive language by hypothyroxinaemic status
    End point description
    Infant thyroxinaemic status was classified as hypothyroxinaemia - a T4 level at or below the 10th percentile, corrected to gestational age subgroup (i.e. ≤25, 26-27, 28-30 weeks) on postnatal days 7, 14 or 28; euthyroid constituted the remainder.
    End point type
    Secondary
    End point timeframe
    Hypothyroxinaemic status classified during first 28 days of life, neurodevelopment outcome assessed at 2 years of age.
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    496
    498
    Units: Bayley-III
    arithmetic mean (standard deviation)
        Hypothyroxinaemic
    7.3 ± 3
    8.1 ± 3
        Euthyroid
    8.7 ± 3
    8.4 ± 3
    No statistical analyses for this end point

    Secondary: Expressive language by hypothyroxinaemic status

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    End point title
    Expressive language by hypothyroxinaemic status
    End point description
    Infant thyroxinaemic status was classified as hypothyroxinaemia - a T4 level at or below the 10th percentile, corrected to gestational age subgroup (i.e. ≤25, 26-27, 28-30 weeks) on postnatal days 7, 14 or 28; euthyroid constituted the remainder.
    End point type
    Secondary
    End point timeframe
    Hypothyroxinaemic status classified during first 28 days of life, neurodevelopment outcome assessed at 2 years of age.
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    495
    498
    Units: Bayley-III units
    arithmetic mean (standard deviation)
        Hypothyroxinaemic
    7.4 ± 3
    8.1 ± 4
        Euthyroid
    8.6 ± 3
    8.3 ± 3
    No statistical analyses for this end point

    Secondary: Fine motor score by hypothyroxinaemic status

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    End point title
    Fine motor score by hypothyroxinaemic status
    End point description
    Infant thyroxinaemic status was classified as hypothyroxinaemia - a T4 level at or below the 10th percentile, corrected to gestational age subgroup (i.e. ≤25, 26-27, 28-30 weeks) on postnatal days 7, 14 or 28; euthyroid constituted the remainder.
    End point type
    Secondary
    End point timeframe
    Hypothyroxinaemic status classified during first 28 days of life, neurodevelopment outcome assessed at 2 years of age.
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    497
    497
    Units: Bayley-III units
    arithmetic mean (standard deviation)
        Hypothyroxinaemic
    9.3 ± 4
    9.7 ± 3
        Euthyroid
    9.9 ± 3
    10 ± 3
    No statistical analyses for this end point

    Secondary: Gross Motor Score by Hypothyroxinaemic Status

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    End point title
    Gross Motor Score by Hypothyroxinaemic Status
    End point description
    Infant thyroxinaemic status was classified as hypothyroxinaemia - a T4 level at or below the 10th percentile, corrected to gestational age subgroup (i.e. ≤25, 26-27, 28-30 weeks) on postnatal days 7, 14 or 28; euthyroid constituted the remainder.
    End point type
    Secondary
    End point timeframe
    Hypothyroxinaemic status classified during first 28 days of life, neurodevelopment outcome assessed at 2 years of age.
    End point values
    Sodium Chloride Sodium Iodide
    Number of subjects analysed
    497
    498
    Units: Bayley-III units
    arithmetic mean (standard deviation)
        Hypothyroxinaemic
    7.7 ± 3
    7.7 ± 3
        Euthyroid
    8.3 ± 3
    8.1 ± 3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SUSARS and AEs were reported for each infant for the period of the trial solutions supplementation plus two weeks or discharge from hospital (which ever was first).
    Adverse event reporting additional description
    The infants were all in neonatal intensive care units during the trial. Many adverse events were anticipated as all infants were extremely preterm. A guidance sheet listed the anticipated events that did not require specific recording for the purposes of the I2S2 trial.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    we did not use one
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Placebo arm
    Reporting group description
    These infants were all extremely preterm and have an anticipated death rate of 10-11% . Anticipated adverse events were recorded in the clinical notes and on the case report form. Some screening laboratories instigate follow-up tests at TSH levels ≥6 mU/l, so we classified this level as an adverse event to ensure that these infants were quickly investigated by local units; such mildly raised TSHs were not considered clinically as an adverse events although they were recorded as such for trial monitoring purposes.

    Reporting group title
    Intervention arm
    Reporting group description
    These infants were all extremely preterm and have an anticipated death rate of 10-11% . Anticipated adverse events were recorded in the clinical notes and on the case report form. Some screening laboratories instigate follow-up tests at TSH levels ≥6 mU/l, so we classified this level as an adverse event to ensure that these infants were quickly investigated by local units; such mildly raised TSHs were not considered clinically as an adverse events although they were recorded as such for trial monitoring purposes.

    Serious adverse events
    Placebo arm Intervention arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 628 (0.80%)
    13 / 631 (2.06%)
         number of deaths (all causes)
    66
    65
         number of deaths resulting from adverse events
    0
    0
    Investigations
    miscellaneous
    Additional description: persistent metabolic acidosis, fluctuating sodium levels, intrahepatic calcification, hypernatraemia, fulminating NEC, GI obstruction, abdominal mass, pleural effusion, clot in aorta, aortic sleeve thrombus, hypoglycaemia
         subjects affected / exposed
    5 / 628 (0.80%)
    13 / 631 (2.06%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo arm Intervention arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 628 (3.66%)
    45 / 631 (7.13%)
    Endocrine disorders
    TSH levels =>6mU/L
    Additional description: All infants who has a TSH level=>6 mU/L were recorded as an adverse event solely to ensure that such infants were quickly monitored locally; they were NOTconsidered an adverse event from a clinical perspective.
    alternative assessment type: Systematic
         subjects affected / exposed
    23 / 628 (3.66%)
    45 / 631 (7.13%)
         occurrences all number
    23
    45

    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
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