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    Clinical Trial Results:
    Amino acid regimen and intravenous lipid composition in preterm parenteral nutrition: a randomised double blind controlled trial of Nutritional Evaluation and Optimisation in Neonates.

    Summary
    EudraCT number
    2009-016731-34
    Trial protocol
    GB  
    Global end of trial date
    23 Dec 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Nov 2016
    First version publication date
    18 Nov 2016
    Other versions
    Summary report(s)
    Final report
    NIHR final report

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO1413
    Additional study identifiers
    ISRCTN number
    ISRCTN29665319
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Room 221, Medical School Building, Norfolk Place, London, United Kingdom, W2 1PG
    Public contact
    Dr Sabita Uthaya, Chelsea and Westminster NHS Foundation Trust, London, UK Imperial College London, +44 (0)2033157975, s.uthaya@imperial.ac.uk
    Scientific contact
    Dr Sabita Uthaya, Chelsea and Westminster NHS Foundation Trust, London, UK Imperial College London, +44 (0)2033157975, s.uthaya@imperial.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
    23 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Amino acid arm: Does immediate rather than incremental introduction of Recommended Daily Intake (RDI) of amino acids compared to current practice of incremental and low intake in extremely preterm infants result in a greater accrual of non-adipose (lean) body mass? Lipid arm: Does 20% SMOFlipid (Soy bean, Medium chain triglycerides, Olive oil and Fish oil combination, a 3rd generation lipid with a lower ratio of n6 to n3 fatty acids and liver protective) compared to 20% Intralipid (currently used lipid formulation composed of Soy bean oil) in extremely preterm infants reduce Intrahepatocellular lipid (IHCL) at term age equivalent? The three main components of nutrition or 'macronutrients' are carbohydrates, lipids and protein. Amino acids are the 'building blocks' of protein and important for the development of lean tissue such as muscle. Intrahepatocellular lipid (IHCL) or fatty liver is associated with problems such as diabetes and insulin resistance. We have shown that p
    Protection of trial subjects
    All infants recruited to the trial were inpatients in Neonatal Intensive Care Units (NICU) at the time of recruitment and throughout parenteral nutrition. This is in line with routine care for extreme preterm infants. Participation in the trial did not introduce any additional distress over and above routine care.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Jul 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: 168
    Worldwide total number of subjects
    168
    EEA total number of subjects
    168
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    168
    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
    Recruitment lasted for 3 years, the first patient was recruited on 06/07/2010 and the last patient on 31/07/2013. A total of 168 infants were recruited from four UK sites; Chelsea and Westminster hospital, West Middlesex hospital, Northwick Park Hospital and Medway Maritime Hospital.

    Pre-assignment
    Screening details
    460 infants below 31 weeks gestational age were admitted during the trial period. Of the 382 infants meeting the eligibility criteria, 168 were randomised to the trial. Reasons for non recruitment: declined (73), recruited to another trial (3), missed/pharmacy unavailable (46), missed/not approached (33), unknown (59).

    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, Subject
    Blinding implementation details
    Unblinded trial PN was delivered to the pharmacy department at each participating centre. Trained pharmacy staff were responsible for blinding the trial parenteral nutrition (PN) prior to dispensing the supply for administration to each infant. Secure copies of the randomisation list were held by each pharmacy team in case of the need for emergency unblinding. There was no requirement for unblinding at any point over the course of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Inc-AA / Intralipid
    Arm description
    Incremental amino acid and 20% Intralipid
    Arm type
    Active comparator

    Investigational medicinal product name
    Vaminolact (incremental)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Inc-AA arms protein content starts at 1.5 g/kg/day on Day 1, increases to 1.9 g/kg/day on day to and 2.4 g/kg/day on day 3 onwards. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Investigational medicinal product name
    20% Intralipid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Inc-AA arms protein content starts at 1.5 g/kg/day on Day 1, increases to 1.9 g/kg/day on day to and 2.4 g/kg/day on day 3 onwards. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Arm title
    Inc-AA/SMOFlipid
    Arm description
    Incremental amino acid and 20% SMOF lipid
    Arm type
    Experimental

    Investigational medicinal product name
    Vaminolact (incremental)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Inc-AA arms protein content starts at 1.5 g/kg/day on Day 1, increases to 1.9 g/kg/day on day to and 2.4 g/kg/day on day 3 onwards. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Investigational medicinal product name
    SMOFlipid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Inc-AA arms protein content starts at 1.5 g/kg/day on Day 1, increases to 1.9 g/kg/day on day to and 2.4 g/kg/day on day 3 onwards. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Arm title
    Imm-RDI/Intralipid
    Arm description
    Recommended Daily Intake of amino acids and 20% Intralipid
    Arm type
    Experimental

    Investigational medicinal product name
    Vaminolact (RDI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Imm-RDI arms protein content starts at 3.2 g/kg/day on Day 1 and continues at this dose. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Investigational medicinal product name
    20% Intralipid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Imm-RDI arms protein content starts at 3.2 g/kg/day on Day 1, and continues at this dose. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Arm title
    Imm-RDI/SMOFlipid
    Arm description
    Recommended Daily Intake of amino acids and 20% SMOF lipid
    Arm type
    Experimental

    Investigational medicinal product name
    Vaminolact (RDI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Imm-RDI arms protein content starts at 3.2 g/kg/day on Day 1 and continues at this dose. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Investigational medicinal product name
    SMOFlipid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Parenteral nutrition will be administered to an infant until milk feeds of 150ml/kg/day for at least 24 hrs are established. In the Imm-RDI arms protein content starts at 3.2 g/kg/day on Day 1 and continues at this dose. Lipid content is the same in all arms (2g/kg/day on day 1, increasing to 3g/kg/day on day 2 onwards), only the type of lipid varies

    Number of subjects in period 1
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Started
    42
    42
    41
    43
    Completed
    34
    28
    34
    37
    Not completed
    8
    14
    7
    6
         Parents participating in conflicting trial
    -
    1
    -
    -
         Physician decision
    -
    1
    1
    -
         Still inpatient at 44 weeks
    1
    2
    1
    -
         Adverse event, serious fatal
    3
    7
    3
    3
         Consent withdrawn by subject
    -
    1
    -
    1
         Lost to follow-up
    4
    2
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inc-AA / Intralipid
    Reporting group description
    Incremental amino acid and 20% Intralipid

    Reporting group title
    Inc-AA/SMOFlipid
    Reporting group description
    Incremental amino acid and 20% SMOF lipid

    Reporting group title
    Imm-RDI/Intralipid
    Reporting group description
    Recommended Daily Intake of amino acids and 20% Intralipid

    Reporting group title
    Imm-RDI/SMOFlipid
    Reporting group description
    Recommended Daily Intake of amino acids and 20% SMOF lipid

    Reporting group values
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid Total
    Number of subjects
    42 42 41 43 168
    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
    Infant age at birth expressed as gestational age in weeks
    Units: weeks
        arithmetic mean (standard deviation)
    27.8 ± 1.9 27.5 ± 2.4 28.1 ± 2.1 27.8 ± 2.1 -
    Gender categorical
    Units: Subjects
        Female
    15 16 19 21 71
        Male
    27 26 22 22 97
    Multiple births
    Units: Subjects
        Yes
    6 6 9 15 36
        No
    36 36 32 28 132
    Mother’s ethnicity
    Units: Subjects
        White
    17 19 20 21 77
        Asian
    13 7 13 12 45
        Black
    6 13 6 6 31
        Mixed
    2 2 1 2 7
        Other
    3 0 1 2 6
        Missing
    1 1 0 0 2
    Mode of delivery
    Units: Subjects
        Vaginal
    8 18 16 17 59
        Elective caesarean
    7 3 4 2 16
        Emergency caesarean
    27 21 21 24 93
    Antenatal steroids
    Units: Subjects
        Yes
    30 34 32 35 131
        No
    7 6 7 4 24
        Unknown
    5 2 2 4 13
    Birthweight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    1.03 ± 0.29 1.05 ± 0.34 1.04 ± 0.28 1.06 ± 0.29 -
    Birth length
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    35 ± 3.6 34.6 ± 4.2 35.3 ± 3.8 35.2 ± 5.2 -
    Head circumference
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    25.2 ± 2 25 ± 3 25.3 ± 1.9 25.6 ± 2.9 -
    Mother's age
    Units: years
        arithmetic mean (standard deviation)
    32.9 ± 5.3 31.3 ± 7.7 32.9 ± 6.3 32.5 ± 6.6 -
    Mother's weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    67.3 ± 13.4 65.9 ± 11.4 64 ± 12.7 68.5 ± 15.2 -
    Mother’s height
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    161.9 ± 7.8 164.9 ± 7.7 161.3 ± 9.2 164.5 ± 8.6 -
    Father’s weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    80.8 ± 10.7 82.3 ± 13.2 85.3 ± 16.1 86.3 ± 14.9 -
    Father's height
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    178.4 ± 6.5 179.6 ± 6.8 175.7 ± 10 182 ± 9.7 -
    Time from birth to starting Parenteral Nutrition
    Units: hour(s)
        median (inter-quartile range (Q1-Q3))
    18.4 (12.3 to 22.7) 19.5 (13.6 to 22.8) 20.4 (12.6 to 23.6) 17.7 (13 to 22.4) -
    Birthweight (z-score)
    Units: z-score
        arithmetic mean (standard deviation)
    -0.2 ± 0.9 0.1 ± 1 -0.2 ± 1 0 ± 0.9 -
    Birth length (z-score)
    Units: z-score
        arithmetic mean (standard deviation)
    -1 ± 1 -0.9 ± 1.2 -1.1 ± 1 -0.8 ± 1.5 -
    Head circumference (z-score)
    Units: z-score
        arithmetic mean (standard deviation)
    -0.5 ± 0.9 -0.3 ± 1 -0.7 ± 0.9 -0.2 ± 1.6 -

    End points

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    End points reporting groups
    Reporting group title
    Inc-AA / Intralipid
    Reporting group description
    Incremental amino acid and 20% Intralipid

    Reporting group title
    Inc-AA/SMOFlipid
    Reporting group description
    Incremental amino acid and 20% SMOF lipid

    Reporting group title
    Imm-RDI/Intralipid
    Reporting group description
    Recommended Daily Intake of amino acids and 20% Intralipid

    Reporting group title
    Imm-RDI/SMOFlipid
    Reporting group description
    Recommended Daily Intake of amino acids and 20% SMOF lipid

    Primary: Non-adipose mass

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    End point title
    Non-adipose mass
    End point description
    Non-adipose (lean) body mass measured by whole body magnetic resonance imaging (MRI)
    End point type
    Primary
    End point timeframe
    Measured at term age equivalent, i.e. 37-44 weeks gestational age.
    End point values
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Number of subjects analysed
    34
    28
    34
    37
    Units: gram(s)
        arithmetic mean (confidence interval 95%)
    2450 (2246 to 2655)
    2337 (2164 to 2510)
    2344 (2244 to 2444)
    2485 (2327 to 2643)
    Statistical analysis title
    Multiple regression
    Statistical analysis description
    A multiple regression was used with non-adipose mass (g) as the dependent variable and amino acid group (Inc-AA or Imm-RDI), lipid group (Intralipid or SMOFlipid), stratifying variables (gestational age, birthweight and centre), sex and age at assessment as the independent variables. An interaction term was added to assess if the effect of amino acid regimen is influenced by lipid type.
    Comparison groups
    Inc-AA / Intralipid v Inc-AA/SMOFlipid v Imm-RDI/Intralipid v Imm-RDI/SMOFlipid
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.05
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -108
         upper limit
    111
    Notes
    [1] - 2x2 Factorial design. Comparison for non-adipose mass based on Inc-AA versus Imm-RDI groups.

    Primary: Intrahepatocellular Lipid (IHCL)

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    End point title
    Intrahepatocellular Lipid (IHCL)
    End point description
    Intrahepatocellular lipid content (IHCL) measured by hepatic magnetic resonance spectroscopy (MRS)
    End point type
    Primary
    End point timeframe
    Measured at term age equivalent, i.e. 37-44 weeks gestational age
    End point values
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Number of subjects analysed
    34
    28
    34
    36
    Units: not applicable
        arithmetic mean (confidence interval 95%)
    0.6 (0.4 to 0.9)
    0.7 (0.5 to 1)
    0.5 (0.4 to 0.6)
    0.5 (0.3 to 0.7)
    Statistical analysis title
    Multiple regression
    Statistical analysis description
    A multiple regression was used with IHCL content (natural logarithmic scale) as the dependent variable and amino acid group (Inc-AA or Imm-RDI), lipid group (Intralipid or SMOFlipid), stratifying variables (gestational age, birthweight and centre), sex and age at assessment as the independent variables. An interaction term was added to assess if the effect of amino acid regimen is influenced by lipid type.
    Comparison groups
    Inc-AA / Intralipid v Inc-AA/SMOFlipid v Imm-RDI/Intralipid v Imm-RDI/SMOFlipid
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.05
    Method
    Regression, Linear
    Parameter type
    geometric mean ratio
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.6
    Notes
    [2] - 2 x 2 Factorial trial IHCL based comparison of Intralipid and SMOFlipid arms

    Secondary: Total cerebral volume

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    End point title
    Total cerebral volume
    End point description
    End point type
    Secondary
    End point timeframe
    Term age equivalent, i.e. 37-44 weeks gestational age
    End point values
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Number of subjects analysed
    13
    10
    11
    15
    Units: cm^3
        arithmetic mean (confidence interval 95%)
    468 (419 to 518)
    480 (425 to 534)
    468 (414 to 523)
    511 (440 to 583)
    Statistical analysis title
    Multiple regression
    Comparison groups
    Inc-AA/SMOFlipid v Imm-RDI/Intralipid v Inc-AA / Intralipid v Imm-RDI/SMOFlipid
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.05
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42
         upper limit
    71
    Notes
    [3] - 2X2 factorial trial Analysis based on comparison of Imm-AA and Imm-RDI arms

    Secondary: Whole-brain volume

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    End point title
    Whole-brain volume
    End point description
    End point type
    Secondary
    End point timeframe
    Term age equivalent, i.e. 37-44 weeks gestational age
    End point values
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Number of subjects analysed
    13
    10
    11
    15
    Units: cm^3
        arithmetic mean (confidence interval 95%)
    339 (304 to 373)
    352 (319 to 385)
    344 (296 to 393)
    365 (321 to 410)
    Statistical analysis title
    Multiple regression
    Comparison groups
    Inc-AA / Intralipid v Inc-AA/SMOFlipid v Imm-RDI/Intralipid v Imm-RDI/SMOFlipid
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    < 0.05
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29
         upper limit
    47
    Notes
    [4] - 2X2 factorial design Analysis based on comparison of Inc-AA and Imm-RDI arms

    Secondary: Posterior fossa volume

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    End point title
    Posterior fossa volume
    End point description
    End point type
    Secondary
    End point timeframe
    Term age equivalent, i.e. 37-44 weeks gestational age
    End point values
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Number of subjects analysed
    13
    10
    11
    15
    Units: cm^3
        arithmetic mean (confidence interval 95%)
    30 (26 to 33)
    31 (28 to 34)
    30 (27 to 34)
    35 (29 to 38)
    Statistical analysis title
    Multiple regression
    Comparison groups
    Inc-AA / Intralipid v Inc-AA/SMOFlipid v Imm-RDI/Intralipid v Imm-RDI/SMOFlipid
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.05
    Method
    Regression, Linear
    Parameter type
    Median difference (final values)
    Point estimate
    1.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.99
         upper limit
    4.87
    Notes
    [5] - 2X2 factorial design Analysis based on comparison of Inc-AA and Imm-RDI arms

    Secondary: QUICKI

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    End point title
    QUICKI
    End point description
    Metabolic index of insulin resistance at term age equivalent (Quantitative insulin-sensitivity check index: QUICKI), calculated using fasting serum glucose and insulin.
    End point type
    Secondary
    End point timeframe
    Term age equivalent (37-44 weeks gestational age)
    End point values
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Number of subjects analysed
    11
    6
    11
    11
    Units: not applicable
        arithmetic mean (confidence interval 95%)
    0.18 (0.17 to 0.19)
    0.19 (0.18 to 0.2)
    0.19 (0.18 to 0.2)
    0.18 (0.17 to 0.2)
    Statistical analysis title
    Multiple regression
    Comparison groups
    Inc-AA / Intralipid v Inc-AA/SMOFlipid v Imm-RDI/Intralipid v Imm-RDI/SMOFlipid
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    < 0.05
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.02
    Notes
    [6] - 2 x 2 factorial design Analysis based on comparison of Intralipid and SMOFlipid arms

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation to term age equivalent, i.e. 37-44 weeks gestational age
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Inc-AA / Intralipid
    Reporting group description
    Incremental amino acid and 20% Intralipid

    Reporting group title
    Inc-AA/SMOFlipid
    Reporting group description
    Incremental amino acid and 20% SMOF lipid

    Reporting group title
    Imm-RDI/Intralipid
    Reporting group description
    Recommended Daily Intake of amino acids and 20% Intralipid

    Reporting group title
    Imm-RDI/SMOFlipid
    Reporting group description
    Recommended Daily Intake of amino acids and 20% SMOF lipid

    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: This trial evaluated standard treatments used within their licensed indications so it was not necessary to report and assess non-Serious AEs.
    Serious adverse events
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 42 (19.05%)
    13 / 42 (30.95%)
    8 / 41 (19.51%)
    11 / 43 (25.58%)
         number of deaths (all causes)
    3
    7
    3
    3
         number of deaths resulting from adverse events
    Congenital, familial and genetic disorders
    Chromosome abnormality
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
    3 / 43 (6.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    Convulsion neonatal
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    cot death
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileal perforation
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising enterocolitis
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
    4 / 43 (9.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Inc-AA / Intralipid Inc-AA/SMOFlipid Imm-RDI/Intralipid Imm-RDI/SMOFlipid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2010
    Protocol version 2 Clarifications implemented following review by the Trial Steering Committee (TSC): a) clarification that randomisation would be performed by minimisation with 25% chance of random allocation b) randomisation to be stratified by birthweight in addition to existing factors (centre and gestational age at birth) c) addition of a monthly evaluation to assess trace elements for infants on PN for > 28 days d) Addition of a metabonomic substudy e) Administrative corrections
    28 Oct 2010
    a) Additional blood samples on days 1 and 5 of life to assess inflammatory markers and lipid profile: The intention was to conduct a substudy to collect these samples at the lead site but it was never implemented. b) Clarification of randomisation time window. The protocol previously stated that infants must be randomised within 12 hours of birth. The purpose of this time window was to allow adequate time for preparation and dispensing of trial PN. The time window was revised for this version of the protocol so that infants needed to be randomised in enough time to allow administration of PN within 24 hours. c) Administrative corrections.
    16 Oct 2012
    The protocol was amended to include a follow-up visit for neurodevelopmental outcomes at 2 years corrected age using the Bayley Scale of Infant Development, the Hammersmith Optimality Score as well as parental questionnaires (Social-Emotional scale of the Bayley Scales and the Quantitative Checklist for Autism in Toddlers). A funding application for this additional visit was not successful, so the additional visit was not implemented.

    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/27099248
    http://www.ncbi.nlm.nih.gov/pubmed/27030860
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