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    Clinical Trial Results:
    Determination of the rhIGF-1/rhIGFBP-3 Dose, Administered as a Continuous Infusion, Required to Establish and Maintain Longitudinal Serum IGF-1 Levels Within Physiological Levels in Premature Infants, to Prevent Retinopathy of Prematurity A Phase 2, Randomized Controlled, Assessor-blind, Dose-confirming, Pharmacokinetic, Safety and Efficacy, Multicenter Study

    Summary
    EudraCT number
    		 2007-007872-40
    Trial protocol
    		 SE   GB   IT   NL   PL  
    Global end of trial date
    30 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2016
    First version publication date
    15 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ROPP-2008-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01096784
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Premacure AB, A Member of the Shire Group of Companies
    Sponsor organisation address
    300 Shire Way, Lexington, Massachusetts, United States, 02421
    Public contact
    Study Physician, Premacure AB, A Member of the Shire Group of Companies, ClinicalTransparency@shire.com
    Scientific contact
    Study Physician, Premacure AB, A Member of the Shire Group of Companies, ClinicalTransparency@shire.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To determine the effect of recombinant human insulin-like growth factor-1 (rhIGF-1)/recombinant human insulin-like growth factor binding protein-3 (rhIGFBP-3) on the severity of retinopathy of prematurity (ROP) as compared to the severity of ROP in an untreated control population. •To evaluate the dose of rhIGF-1/rhIGFBP-3, administered by continuous intravenous (IV) infusion, required to reach and maintain a physiological range of serum IGF-1 of 28-109 microgram per liter (mcg/L), defined as the in utero levels of insulin-like growth factor-1 (IGF-1) for corresponding gestational age (GA) in a normal population. •To determine serum concentrations of IGF-1 and associated pharmacokinetic parameters after continuous IV infusion of rhIGF-1/rhIGFBP-3.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Sweden: 24
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Italy: 56
    Country: Number of subjects enrolled
    Netherlands: 3
    Worldwide total number of subjects
    121
    EEA total number of subjects
    99
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    121
    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 study was conducted in multiple centres in Italy, the Netherlands, Poland, Sweden, the United Kingdom and the United States between 19 September 2014 and 30 March 2016.

    Pre-assignment
    Screening details
    		 A total of 121 subjects were enrolled and randomized into the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Assessor blinded only for the primary endpoint.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rhIGF-1/rhIGFBP-3
    Arm description
    		 Subjects received rhIGF-I/rhIGFBP-3 250 microgram per kilogram (mcg/kg) for 24 hours through continuous IV infusion from Day 0 up to 29 weeks 6 days of post-menstrual age (PMA).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mecasermin rinfabate
    Investigational medicinal product code
    Other name
    rhIGF-1/rhIGFBP-3
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rhIGF-I/rhIGFBP-3 250 mcg/kg for 24 hours through continuous IV infusion from Day 0 up to 29 weeks 6 days of PMA.

    Arm title
    		 Standard of Care (Control)
    Arm description
    		 Subjects in this control group do not received any treatment other than the standard care.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Started
    61
    60
    Completed
    46
    46
    Not completed
    15
    14
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    11
    9
         Protocol Deviation
    2
    2
         Administrative Decision
    -
    1
         Other Unspecified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rhIGF-1/rhIGFBP-3
    Reporting group description
    		 Subjects received rhIGF-I/rhIGFBP-3 250 microgram per kilogram (mcg/kg) for 24 hours through continuous IV infusion from Day 0 up to 29 weeks 6 days of post-menstrual age (PMA).

    Reporting group title
    Standard of Care (Control)
    Reporting group description
    		 Subjects in this control group do not received any treatment other than the standard care.

    Reporting group values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control) Total
    Number of subjects
    		 61 60
    Age categorical
    Units: Subjects
    Age continuous
    Gestational age was mentioned.
    Units: weeks
        arithmetic mean (standard deviation)
    		 25.6 ( 1.207 ) 25.62 ( 1.397 ) -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    		 22 21 43
        Male
    		 39 39 78

    End points

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    End points reporting groups
    Reporting group title
    rhIGF-1/rhIGFBP-3
    Reporting group description
    		 Subjects received rhIGF-I/rhIGFBP-3 250 microgram per kilogram (mcg/kg) for 24 hours through continuous IV infusion from Day 0 up to 29 weeks 6 days of post-menstrual age (PMA).

    Reporting group title
    Standard of Care (Control)
    Reporting group description
    		 Subjects in this control group do not received any treatment other than the standard care.

    Primary: Severity of Retinopathy of Prematurity (ROP) as Compared to the Severity of ROP in an Untreated Control Population

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    End point title
    		 Severity of Retinopathy of Prematurity (ROP) as Compared to the Severity of ROP in an Untreated Control Population
    End point description
    ROP was measured by central exams with fundus photography. Maximum severity of ROP stage across all retinal examinations included International Classification of Retinopathy of Prematurity, a 5 stage system, for the classification of ROP with 7 different outcomes of the ROP stage in each retinal examination: 0, 1, 2, 3, 3+, 4, and 5. This is an ordinal scale with higher numbers indicating a more severe outcome. Full analysis set (FAS) included all randomized subjects who received the study drug and subjects in the control group who received Standard of Care.
    End point type
    Primary
    End point timeframe
    From 31 weeks PMA up to 40 weeks PMA End of Study (EOS) +/- 4 days
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: Subjects
        ROP of Stage "0"
    14
    24
        ROP of Stage "1"
    4
    4
        ROP of Stage "2"
    17
    13
        ROP of Stage "3"
    6
    3
        ROP of Stage "3+"
    6
    6
        ROP of Stage "4"
    0
    0
        ROP of Stage "5"
    0
    0
        Missing
    14
    10
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Standard of Care (Control) v rhIGF-1/rhIGFBP-3
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0642
    Method
    		 CMH Row Mean Score Test
    Confidence interval

    Secondary: Time to Discharge from Neonatal Intensive Care (TDNIC)

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    End point title
    		 Time to Discharge from Neonatal Intensive Care (TDNIC)
    End point description
    FAS with number of subjects evaluable for this outcome.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    37
    31
    Units: Days
        median (full range (min-max))
    82 (69 to 96)
    74 (69 to 93)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Bronchopulmonary Dysplasia (BPD)

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    End point title
    		 Number of Subjects With Bronchopulmonary Dysplasia (BPD)
    End point description
    Severity of BPD as mild, moderate and severe were based on the National Institute of Child Health and Human Development (NICHD) guidelines for preterm infants born at gestational age (GA) less than (<) 32 weeks. Mild: oxygen requirement during the first 28 days but in room air at PMA 36 weeks or discharge to home, whichever comes first. Moderate BPD: oxygen requirement during the first 28 days and oxygen <30 percent (%) at PMA 36 weeks or discharge to home, whichever comes first. Severe BPD: oxygen requirement during the first 28 days and oxygen greater than equal (≥)30% through head hood or nasal canula, or continuous positive airway pressure, or mechanical ventilation, or high flow nasal cannula ≥2 L/min at PMA 36 weeks or discharge to home, whichever comes first. FAS with number of subjects evaluable for this outcome.
    End point type
    Secondary
    End point timeframe
    36 Weeks Post Menstrual Age
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    47
    49
    Units: Subjects
        No BPD
    4
    4
        Mild
    23
    16
        Moderate
    9
    5
        Severe
    10
    22
        Unable to determine
    1
    2
    No statistical analyses for this end point

    Secondary: Rate of Change in Body weight

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    End point title
    		 Rate of Change in Body weight
    End point description
    The rate of change is the rate of specific body weight change per day in kilogram (kg). Population analysed was FAS.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: percentage of body weight
        number (confidence interval 95%)
    0.021 (0.019 to 0.022)
    0.023 (0.021 to 0.024)
    No statistical analyses for this end point

    Secondary: Rate of Change in Length

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    End point title
    		 Rate of Change in Length
    End point description
    The rate of change is the length change per day in centimeter (cm). Population analysed was FAS.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: percentage of length
        number (confidence interval 95%)
    0.141 (0.0132 to 0.149)
    0.156 (0.147 to 0.164)
    No statistical analyses for this end point

    Secondary: Rate of Change in Head Circumference

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    End point title
    		 Rate of Change in Head Circumference
    End point description
    The rate of change is the head circumference change per day in centimetre (cm). Population analysed was FAS.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: percentage of head circumference
        number (confidence interval 95%)
    0.115 (0.109 to 0.121)
    0.119 (0.113 to 0.125)
    No statistical analyses for this end point

    Secondary: Brain Development as Assessed by Changes in Brain Volume

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    End point title
    		 Brain Development as Assessed by Changes in Brain Volume
    End point description
    Brain volume was measured using cerebral magnetic resonance imaging (MRI). Brain volume included cerebrospinal volume, gray matter volume, white matter volume, and total cerebellar volume. Population analysed was FAS. Here, n = number of subjects evaluable at each categories for the specific reporting groups.
    End point type
    Secondary
    End point timeframe
    Week 40 PMA/ EOS +/- 4 days
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: cubic centimeter
    arithmetic mean (standard deviation)
        Cerebrospinal Fluid Volume (n = 45, 40)
    87.94 ( 26.788 )
    93.7 ( 25.54 )
        Gray Matter Volume (n = 45, 40)
    206.34 ( 31.797 )
    221.98 ( 33.827 )
        White Matter Volume (n = 45, 40)
    110.23 ( 25.565 )
    117.62 ( 24.422 )
        Total Cerebellar Volume (n = 45, 41)
    18.27 ( 5.302 )
    19.2 ( 4.854 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Intraventricular Hemorrhage (IVH)

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    End point title
    		 Percentage of Subjects With Intraventricular Hemorrhage (IVH)
    End point description
    Development of intraventricular hemorrhage was assessed by cerebral ultrasound and coded as a binary endpoint (presence or absence of IVH). Population analysed was FAS.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: percentage of subjects
    number (not applicable)
        Yes
    19.67
    30
        No
    80.33
    70
    No statistical analyses for this end point

    Secondary: Area Under Curve for Maximum Severity of ROP Stage (AUC for ROP)

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    End point title
    		 Area Under Curve for Maximum Severity of ROP Stage (AUC for ROP)
    End point description
    Integration of the maximum severity of ROP stage and the duration of the time interval with respect to each retinal examination. AUC for the maximum severity of ROP was calculated using the trapezoidal rule. The area between each 2 visits was calculated by multiplying the average of the maximum severities of the 2 visits by the difference in days and analyzed using the van Elteren test. Population analysed was FAS with number of subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    42
    49
    Units: hour*microgram per liter
        arithmetic mean (standard deviation)
    47.95 ( 47.384 )
    32.17 ( 40.151 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Maximum Severity of ROP Stage Greater Than Equal to 3 at any Time During the Study

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    End point title
    		 Percentage of Subjects With Maximum Severity of ROP Stage Greater Than Equal to 3 at any Time During the Study
    End point description
    ROP was measured by central exams with fundus photography. Maximum severity of ROP stage across all retinal examinations included International Classification of Retinopathy of Prematurity, a 5 stage system, for the classification of ROP with 7 different outcomes of the ROP stage in each retinal examination: 0, 1, 2, 3, 3+, 4, and 5. This is an ordinal scale with higher numbers indicating a more severe outcome. Population analysed was FAS.
    End point type
    Secondary
    End point timeframe
    Every 1-2 weeks starting at 31 weeks PMA/ EOS +/- 4 days
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: percentage of subjects
    number (not applicable)
        Yes
    25.53
    18
        No
    74.47
    82
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse Event (TEAE) and Treatment Emergent Serious Adverse Event (TESAE)

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    End point title
    		 Number of Subjects with Treatment Emergent Adverse Event (TEAE) and Treatment Emergent Serious Adverse Event (TESAE)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAE was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product. Safety analysis set (SAF) included all randomized subjects who received the study drug and subjects in the control group who received standard of care, and for whom at least 1 safety assessment was completed.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: Subjects
        Subjects with TEAE
    60
    60
        Subjects with TESAE
    48
    37
    No statistical analyses for this end point

    Secondary: Percentage of Serum IGF-1 concentrations Falling Withing Target Range After Infusion of rhIGF-1/rhIGFBP-3

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    End point title
    		 Percentage of Serum IGF-1 concentrations Falling Withing Target Range After Infusion of rhIGF-1/rhIGFBP-3
    End point description
    Serum samples were collected from treated and control subjects for quantification of IGF-1 using validated immunoassays. Target range of serum IGF-1 was 28-109 mcg/L. Population analysed was FAS.
    End point type
    Secondary
    End point timeframe
    Day 0 to 40 Weeks Post Menstrual Age (EOS)
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: percentage of serum concentration
        number (not applicable)
    66.23
    6.28
    No statistical analyses for this end point

    Secondary: Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3

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    End point title
    		 Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3
    End point description
    Population analysed was FAS. Here n = number of subjects evaluable at each categories for the specific reporting groups.
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 40 PMA/EOS +/- 4 days
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: number
    arithmetic mean (standard deviation)
        DAY 0 (N = 60, 60)
    494.2 ( 200.38 )
    469.9 ( 180.52 )
        WEEK 40 (N = 47, 46)
    830.1 ( 200.17 )
    882.1 ( 274.43 )
    No statistical analyses for this end point

    Secondary: Serum concentrations of Acid Labile Sub-unit (ALS) After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3

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    End point title
    		 Serum concentrations of Acid Labile Sub-unit (ALS) After Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3
    End point description
    Population analysed was FAS. Here, n = number of subjects evaluable at each categories for the specific reporting groups.
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 40 PMA/ EOS +/- 4 days
    End point values
    		 rhIGF-1/rhIGFBP-3 Standard of Care (Control)
    Number of subjects analysed
    61
    60
    Units: microgram per liter
    arithmetic mean (standard deviation)
        DAY 7 (N = 60, 60)
    411.9 ( 237.91 )
    500.3 ( 350.59 )
        WEEK 40 (N = 47, 46)
    1804.6 ( 629.61 )
    2114.3 ( 941.94 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 0 upto 4 days from PMA 40 Weeks
    Adverse event reporting additional description
    Event desc
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 nil
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    rhIGF-I/rhIGFBP-3
    Reporting group description
    		 Subjects received rhIGF-I/rhIGFBP-3 250 mcg/kg for 24 hours through continuous IV infusion from Day 0 up to 29 weeks 6 days of PMA.

    Reporting group title
    Standard of Care (Control)
    Reporting group description
    		 Subjects in this control group do not received any treatment other than the standard care.

    Serious adverse events
    		 rhIGF-I/rhIGFBP-3 Standard of Care (Control)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 61 (78.69%)
    37 / 60 (61.67%)
         number of deaths (all causes)
    12
    7
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Neonatal hypotension
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vena cava thrombosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infantile apnoeic attack
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal aspiration
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal respiratory distress syndrome
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal respiratory failure
         subjects affected / exposed
    7 / 61 (11.48%)
    9 / 60 (15.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 13
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Pleurisy
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary interstitial emphysema syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Pco2 increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Patent ductus arteriosus
         subjects affected / exposed
    13 / 61 (21.31%)
    14 / 60 (23.33%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 14
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac disorders
    Bradycardia neonatal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac hypertrophy
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage neonatal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion neonatal
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intraventricular haemorrhage neonatal
         subjects affected / exposed
    7 / 61 (11.48%)
    8 / 60 (13.33%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Periventricular leukomalacia
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulation disorder neonatal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia neonatal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy of prematurity
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Intra-Abdominal haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meconium ileus
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising enterocolitis neonatal
         subjects affected / exposed
    6 / 61 (9.84%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure neonatal
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Infections and infestations
    Citrobacter sepsis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enterococcal sepsis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Group b streptococcus neonatal sepsis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal pneumonia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis neonatal
         subjects affected / exposed
    7 / 61 (11.48%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Serratia sepsis
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    9 / 61 (14.75%)
    7 / 60 (11.67%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hyperammonaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 rhIGF-I/rhIGFBP-3 Standard of Care (Control)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 61 (95.08%)
    60 / 60 (100.00%)
    Vascular disorders
    Neonatal hypotension
         subjects affected / exposed
    23 / 61 (37.70%)
    15 / 60 (25.00%)
         occurrences all number
    33
    27
    Pregnancy, puerperium and perinatal conditions
    Jaundice neonatal
         subjects affected / exposed
    28 / 61 (45.90%)
    30 / 60 (50.00%)
         occurrences all number
    34
    38
    Poor weight gain neonatal
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 60 (6.67%)
         occurrences all number
    3
    4
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    9 / 61 (14.75%)
    4 / 60 (6.67%)
         occurrences all number
    15
    5
    Infusion site extravasation
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences all number
    1
    8
    Oedema peripheral
         subjects affected / exposed
    9 / 61 (14.75%)
    1 / 60 (1.67%)
         occurrences all number
    11
    1
    Reproductive system and breast disorders
    Oedema genital
         subjects affected / exposed
    8 / 61 (13.11%)
    1 / 60 (1.67%)
         occurrences all number
    9
    2
    Respiratory, thoracic and mediastinal disorders
    Atelectasis neonatal
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 60 (6.67%)
         occurrences all number
    3
    4
    Bronchopulmonary dysplasia
         subjects affected / exposed
    34 / 61 (55.74%)
    37 / 60 (61.67%)
         occurrences all number
    37
    42
    Bronchospasm
         subjects affected / exposed
    2 / 61 (3.28%)
    8 / 60 (13.33%)
         occurrences all number
    2
    11
    Hypocapnia
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 60 (6.67%)
         occurrences all number
    3
    5
    Infantile apnoeic attack
         subjects affected / exposed
    26 / 61 (42.62%)
    16 / 60 (26.67%)
         occurrences all number
    42
    32
    Neonatal hypoxia
         subjects affected / exposed
    14 / 61 (22.95%)
    13 / 60 (21.67%)
         occurrences all number
    17
    21
    Neonatal respiratory acidosis
         subjects affected / exposed
    10 / 61 (16.39%)
    5 / 60 (8.33%)
         occurrences all number
    30
    11
    Neonatal respiratory failure
         subjects affected / exposed
    9 / 61 (14.75%)
    5 / 60 (8.33%)
         occurrences all number
    11
    5
    Neonatal respiratory distress syndrome
         subjects affected / exposed
    27 / 61 (44.26%)
    32 / 60 (53.33%)
         occurrences all number
    31
    41
    Neonatal tachypnoea
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 60 (6.67%)
         occurrences all number
    2
    5
    Pulmonary haemorrhage
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 60 (0.00%)
         occurrences all number
    4
    0
    Pulmonary hypertension
         subjects affected / exposed
    6 / 61 (9.84%)
    9 / 60 (15.00%)
         occurrences all number
    6
    11
    Pulmonary oedema neonatal
         subjects affected / exposed
    6 / 61 (9.84%)
    1 / 60 (1.67%)
         occurrences all number
    7
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 61 (8.20%)
    6 / 60 (10.00%)
         occurrences all number
    6
    6
    C-Reactive protein increased
         subjects affected / exposed
    5 / 61 (8.20%)
    4 / 60 (6.67%)
         occurrences all number
    6
    5
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    6 / 61 (9.84%)
    9 / 60 (15.00%)
         occurrences all number
    6
    10
    Patent ductus arteriosus
         subjects affected / exposed
    53 / 61 (86.89%)
    45 / 60 (75.00%)
         occurrences all number
    67
    57
    Cardiac disorders
    Neonatal tachycardia
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 60 (0.00%)
         occurrences all number
    8
    0
    Bradycardia neonatal
         subjects affected / exposed
    13 / 61 (21.31%)
    5 / 60 (8.33%)
         occurrences all number
    18
    6
    Nervous system disorders
    Convulsion neonatal
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 60 (5.00%)
         occurrences all number
    3
    3
    Cerebral ventricle dilatation
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    3
    Intraventricular haemorrhage neonatal
         subjects affected / exposed
    11 / 61 (18.03%)
    18 / 60 (30.00%)
         occurrences all number
    13
    19
    Periventricular leukomalacia
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Coagulation disorder neonatal
         subjects affected / exposed
    9 / 61 (14.75%)
    8 / 60 (13.33%)
         occurrences all number
    10
    12
    Anaemia neonatal
         subjects affected / exposed
    46 / 61 (75.41%)
    44 / 60 (73.33%)
         occurrences all number
    210
    157
    Neutropenia neonatal
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 60 (0.00%)
         occurrences all number
    5
    0
    Thrombocytopenia neonatal
         subjects affected / exposed
    12 / 61 (19.67%)
    9 / 60 (15.00%)
         occurrences all number
    15
    13
    Eye disorders
    Retinopathy of prematurity
         subjects affected / exposed
    39 / 61 (63.93%)
    37 / 60 (61.67%)
         occurrences all number
    106
    89
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    5 / 61 (8.20%)
    4 / 60 (6.67%)
         occurrences all number
    5
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 61 (11.48%)
    6 / 60 (10.00%)
         occurrences all number
    9
    6
    Impaired gastric emptying
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences all number
    1
    3
    Inguinal hernia
         subjects affected / exposed
    9 / 61 (14.75%)
    11 / 60 (18.33%)
         occurrences all number
    10
    11
    Umbilical hernia
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 60 (10.00%)
         occurrences all number
    3
    6
    Vomiting neonatal
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 60 (5.00%)
         occurrences all number
    2
    5
    Hepatobiliary disorders
    Hyperbilirubinaemia neonatal
         subjects affected / exposed
    12 / 61 (19.67%)
    14 / 60 (23.33%)
         occurrences all number
    14
    18
    Neonatal cholestasis
         subjects affected / exposed
    2 / 61 (3.28%)
    6 / 60 (10.00%)
         occurrences all number
    2
    6
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 60 (5.00%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    Growth retardation
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences all number
    1
    3
    Osteopenia
         subjects affected / exposed
    6 / 61 (9.84%)
    9 / 60 (15.00%)
         occurrences all number
    6
    9
    Infections and infestations
    Fungal skin infection
         subjects affected / exposed
    3 / 61 (4.92%)
    3 / 60 (5.00%)
         occurrences all number
    6
    6
    Neonatal pneumonia
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences all number
    1
    3
    Pneumonia bacterial
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 60 (8.33%)
         occurrences all number
    4
    6
    Rhinitis
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 60 (5.00%)
         occurrences all number
    5
    6
    Sepsis neonatal
         subjects affected / exposed
    16 / 61 (26.23%)
    15 / 60 (25.00%)
         occurrences all number
    33
    29
    Staphylococcal sepsis
         subjects affected / exposed
    9 / 61 (14.75%)
    12 / 60 (20.00%)
         occurrences all number
    14
    16
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    4 / 61 (6.56%)
    8 / 60 (13.33%)
         occurrences all number
    5
    9
    Feeding disorder neonatal
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences all number
    1
    4
    Hypercalcaemia
         subjects affected / exposed
    4 / 61 (6.56%)
    4 / 60 (6.67%)
         occurrences all number
    5
    8
    Hyperglycaemia
         subjects affected / exposed
    24 / 61 (39.34%)
    28 / 60 (46.67%)
         occurrences all number
    41
    55
    Hypernatraemia
         subjects affected / exposed
    6 / 61 (9.84%)
    11 / 60 (18.33%)
         occurrences all number
    7
    13
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 61 (8.20%)
    4 / 60 (6.67%)
         occurrences all number
    6
    5
    Hypocalcaemia
         subjects affected / exposed
    8 / 61 (13.11%)
    6 / 60 (10.00%)
         occurrences all number
    20
    6
    Hypoglycaemia neonatal
         subjects affected / exposed
    18 / 61 (29.51%)
    19 / 60 (31.67%)
         occurrences all number
    22
    27
    Hypokalaemia
         subjects affected / exposed
    14 / 61 (22.95%)
    11 / 60 (18.33%)
         occurrences all number
    24
    18
    Hypophosphataemia
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 60 (6.67%)
         occurrences all number
    2
    5
    Hypovolaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 60 (5.00%)
         occurrences all number
    1
    4
    Metabolic acidosis
         subjects affected / exposed
    17 / 61 (27.87%)
    22 / 60 (36.67%)
         occurrences all number
    43
    46
    Neonatal hyponatraemia
         subjects affected / exposed
    23 / 61 (37.70%)
    22 / 60 (36.67%)
         occurrences all number
    43
    39

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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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    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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