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    Clinical Trial Results:
    Chlorhexidine Versus Povidone-Iodine For Skin Anitsepsis Prior To Central Venous Catheter Insertion In Preterm Infants: Protocol For A Randomised Trial (The SKA Trial)

    Summary
    EudraCT number
    2011-002962-19
    Trial protocol
    IE  
    Global end of trial date
    19 Dec 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Feb 2019
    First version publication date
    22 Feb 2019
    Other versions
    Summary report(s)
    2% chlorhexidine-70% isopropyl alcohol versus 10% povidone-iodine for insertion site cleaning before central line insertion in preterm infants: a randomised trial

    Trial information

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    Trial identification
    Sponsor protocol code
    SKA 001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College Dublin
    Sponsor organisation address
    Belfield, Dublin, Ireland,
    Public contact
    UCD Clinical Research Centre, UCD Clinical Research Centre, 00353 017164597, peter.doran@ucd.ie
    Scientific contact
    UCD Clinical Research Centre, UCD Clinical Research Centre, 00353 017164597, peter.doran@ucd.ie
    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
    19 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether the use of 2% chlorhexidine in 70% isopropyl alcohol compared to 10% povidone-iodine for skin antisepsis prior to central venous catheter insertion results in fewer catheter related blood stream infections in infants<31 weeks gestation
    Protection of trial subjects
    The decision to insert a central venous cathether and the type of central venous cathether to be inserted were made by the attending clinicians. Central venous cathether were inserted under maximum sterile barrier precautions (sterile gown, sterile gloves, hat and mask and using full-body drape) following local clinical guidelines that were common to both neonatal intensive care units. Central venous catheters s could remain in place when sepsis was suspected. However, if a blood culture was positive, the central venous catheter was removed, the tip (5 cm length, cut using sterile blade) was sent for culture and a further blood culture was taken from a different peripheral site. Infants at both centres suspected of having late onset sepsis were empirically treated with flucloxacillin and gentamicin as a first line. Vancomycin could subsequently be used if catheter-related bloodstream infection was confirmed, and treatment was considered appropriate. Antibiotics for catheter-related bloodstream infection were not given through a central venous catheter that was suspected to be infected.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Sep 2011
    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
    Ireland: 310
    Worldwide total number of subjects
    310
    EEA total number of subjects
    310
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    310
    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
    Subjects were recruited from two stand-alone university maternity hospital: the National Maternaty Hospital, Holles Street, Dublin and the Coombe Women and Infants University Hospital, Dublin.

    Pre-assignment
    Screening details
    Infants born at less than 31 weeks of gestational age were eligible for enrolment if they were undergoing CVC insertion for the first time in the neonatal ICU. Infants with congenital anomalies and infants who had previously undergone CVC insertion before the agent used to clean the insertion site could be randomly assigned were excluded.

    Pre-assignment period milestones
    Number of subjects started
    434 [1]
    Number of subjects completed
    304

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 14
    Reason: Number of subjects
    Consent withdrawn by subject: 32
    Reason: Number of subjects
    Physician decision: 2
    Reason: Number of subjects
    Outborn central venous catheter in situ: 30
    Reason: Number of subjects
    Inborn umbilical venous catheter in delivery room: 2
    Reason: Number of subjects
    No-one to consent: 9
    Reason: Number of subjects
    not approached: 40
    Reason: Number of subjects
    Gestational age was 31 weeks: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 6 subjects excluded after baseline due to meeting exclusion criteria. These were not included in baseline results.
    Period 1
    Period 1 title
    Baseline Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    POV IOD
    Arm description
    Subjects in the PI arm were randomised to be treated with povidone–iodine.
    Arm type
    Experimental

    Investigational medicinal product name
    10% w/w povidone–iodine
    Investigational medicinal product code
    Other name
    Videne 10% w/w antiseptic Solution
    Pharmaceutical forms
    Cutaneous liquid
    Routes of administration
    Cutaneous use, Local use
    Dosage and administration details
    Approximately 3 ml of brown 10% w/w povidone–iodine was poured directly into a sterile dish, and a sterile cotton swab was dipped into it for 1–2 seconds. The swab was squeezed to remove excess solution and used to clean the site for 30 seconds. The area was allowed to dry naturally before CVC insertion.

    Arm title
    CHX-IA
    Arm description
    Subjects in the CHX–IA arm were randomised to be treated with chlorhexidine gluconate/isopropyl alcohol/water solution.
    Arm type
    Experimental

    Investigational medicinal product name
    2% w/v chlorhexidine in 70% v/v isopropyl alcohol
    Investigational medicinal product code
    Other name
    ChoraPrep 2% chlorhexidine w/v/isopropyl alcohol 70% v/v
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Cutaneous use, Local use
    Dosage and administration details
    The CVC insertion site was cleaned with 1 0.67 ml ampoule of 2% w/v chlorhexidine in 70% v/v isopropyl alcohol using a single applicator for 30 seconds and then allowed to dry naturally before CVC insertion. If a second ampoule was used, the reason for use was documented on the CVC checklist.

    Number of subjects in period 1 [2]
    POV IOD CHX-IA
    Started
    156
    148
    Completed
    156
    148
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 6 subjects excluded after baseline due to meeting exclusion criteria. These were not included in baseline results.
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CHX-IA
    Arm description
    Infants randomised to CHX–IA group had the CVC insertion site cleaned with chlorhexidine gluconate/isopropyl alcohol/water solution.
    Arm type
    Experimental

    Investigational medicinal product name
    2% w/v chlorhexidine in 70% v/v isopropyl alcohol
    Investigational medicinal product code
    Other name
    ChoraPrep 2% chlorhexidine w/v/isopropyl alcohol 70% v/v
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Cutaneous use, Local use
    Dosage and administration details
    The CVC insertion site was cleaned with 1 0.67 ml ampoule of 2% w/v chlorhexidine in 70% v/v isopropyl alcohol using a single applicator for 30 seconds and then allowed to dry naturally before CVC insertion. If a second ampoule was used, the reason for use was documented on the CVC checklist.

    Arm title
    POV IOD
    Arm description
    Subjects in the PI arm were treated with povidone–iodine.
    Arm type
    Experimental

    Investigational medicinal product name
    10% w/w povidone–iodine
    Investigational medicinal product code
    Other name
    Videne 10% w/w antiseptic Solution
    Pharmaceutical forms
    Cutaneous liquid
    Routes of administration
    Cutaneous use, Local use
    Dosage and administration details
    Approximately 3 ml of brown 10% w/w povidone–iodine was poured directly into a sterile dish, and a sterile cotton swab was dipped into it for 1–2 seconds. The swab was squeezed to remove excess solution and used to clean the site for 30 seconds. The area was allowed to dry naturally before CVC insertion.

    Number of subjects in period 2
    CHX-IA POV IOD
    Started
    148
    156
    Completed
    148
    156

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    POV IOD
    Reporting group description
    Subjects in the PI arm were randomised to be treated with povidone–iodine.

    Reporting group title
    CHX-IA
    Reporting group description
    Subjects in the CHX–IA arm were randomised to be treated with chlorhexidine gluconate/isopropyl alcohol/water solution.

    Reporting group values
    POV IOD CHX-IA Total
    Number of subjects
    156 148 304
    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
    Units: weeks
        arithmetic mean (standard deviation)
    27 ( 2 ) 27 ( 2 ) -
    Gender categorical
    Units: Subjects
        Female
    87 67 154
        Male
    69 81 150
    Antenatal steroid exposure
    Subjects treated with antanatal steroids
    Units: Subjects
        Exposed
    155 144 299
        Not exposed
    1 4 5
    Caesarean section
    Subjects born by caesarean section
    Units: Subjects
        Born by caesarean section
    100 91 191
        Not born by caesarean section
    56 57 113
    Clinical chorioamnionitis
    Subjects with clinical chorioamnionitis
    Units: Subjects
        Clinical chorioamnionitis
    24 14 38
        No clinical chorioamnionitis
    132 134 266
    Multiple birth
    Subjects who were part of a multiple birth
    Units: Subjects
        Multiple birth
    54 62 116
        No multiple birth
    102 86 188
    Ventilation prerandomisation
    Subjects who were ventilated before randomisation
    Units: Subjects
        Ventilated before randomisation
    78 64 142
        Not ventilated before randomisation
    78 84 162
    CPAP prerandomisation
    Subjects who were administered continuous positive airway pressure before randomisation.
    Units: Subjects
        CPAP before randomisation
    100 102 202
        No CPAP before randomisation
    56 46 102
    UVC as first CVC
    Subjects who received an umbilical venous catheter or a peripherally inserted central catheter as there first CVC.
    Units: Subjects
        UVC
    104 96 200
        PICC
    52 52 104
    Birth weight
    Units: gram(s)
        arithmetic mean (standard deviation)
    1014 ( 326 ) 1017 ( 289 ) -
    Apgar score at 1 min
    The Apgar score at 1 minute post-delivery
    Units: arbitrary
        arithmetic mean (standard deviation)
    6 ( 2 ) 6 ( 2 ) -
    Apgar score at 5 min
    The Apgar score at 1 minute post-delivery
    Units: arbritary
        arithmetic mean (standard deviation)
    8 ( 2 ) 8 ( 2 ) -
    Day of life randomised
    Day of life on which subjects were randomised.
    Units: day
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0) 0 (0 to 1) -
    Number of CVCs per patient
    Number of central venous catheters per subject.
    Units: CVCs
        arithmetic mean (standard deviation)
    3 ( 1 ) 3 ( 1 ) -
    Duration CVC in situ per patient
    Duration of central venous catheter left in situ per subject.
    Units: days
        median (inter-quartile range (Q1-Q3))
    9 (6 to 13) 9 (6 to 12) -

    End points

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    End points reporting groups
    Reporting group title
    POV IOD
    Reporting group description
    Subjects in the PI arm were randomised to be treated with povidone–iodine.

    Reporting group title
    CHX-IA
    Reporting group description
    Subjects in the CHX–IA arm were randomised to be treated with chlorhexidine gluconate/isopropyl alcohol/water solution.
    Reporting group title
    CHX-IA
    Reporting group description
    Infants randomised to CHX–IA group had the CVC insertion site cleaned with chlorhexidine gluconate/isopropyl alcohol/water solution.

    Reporting group title
    POV IOD
    Reporting group description
    Subjects in the PI arm were treated with povidone–iodine.

    Primary: Incidence of catheter-related bloodstream infection per infant

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    End point title
    Incidence of catheter-related bloodstream infection per infant
    End point description
    The primary outcome for our study was the number of infants with a CR-BSI. Infants were diagnosed with a CR-BSI if they were >72 hours of age and had a CVC in situ or removed within the previous 48 hours and met at least one of the following three criteria: ► a recognised pathogen (eg, Staphylococcus aureus and Candida species) in one peripheral blood culture (ie, not taken through CVC) that was not related to an infection at another site (eg, meningitis or skin abscess), ► a common skin commensal (eg, coagulase-negative Staphylococcus (CONS)) cultured from two or more peripheral blood cultures drawn on separate occasions, ► a common skin commensal (eg, CONS) isolated from one peripheral blood culture with a CVC tip culture growing >15 colony-forming units of a pure growth of the same organism.
    End point type
    Primary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: catheter-related bloodstream infections
    10
    8
    Statistical analysis title
    Difference in proportion between arms
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.631
    Method
    Fisher exact
    Confidence interval

    Primary: Incidence of catheter-related bloodstream infection per catheter

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    End point title
    Incidence of catheter-related bloodstream infection per catheter
    End point description
    The primary outcome for our study was the number of infants with a CR-BSI. Infants were diagnosed with a CR-BSI if they were >72 hours of age and had a CVC in situ or removed within the previous 48 hours and met at least one of the following three criteria: ► a recognised pathogen (eg, Staphylococcus aureus and Candida species) in one peripheral blood culture (ie, not taken through CVC) that was not related to an infection at another site (eg, meningitis or skin abscess), ► a common skin commensal (eg, coagulase-negative Staphylococcus (CONS)) cultured from two or more peripheral blood cultures drawn on separate occasions, ► a common skin commensal (eg, CONS) isolated from one peripheral blood culture with a CVC tip culture growing >15 colony-forming units of a pure growth of the same organism.
    End point type
    Primary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: catheter-related bloodstream infections
    10
    10
    Statistical analysis title
    Difference in proportion between arms
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.824
    Method
    Fisher exact
    Confidence interval

    Primary: Catheter-related bloodstream infection per 1000 catheter days

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    End point title
    Catheter-related bloodstream infection per 1000 catheter days [1]
    End point description
    The primary outcome for our study was the number of infants with a CR-BSI. Infants were diagnosed with a CR-BSI if they were >72 hours of age and had a CVC in situ or removed within the previous 48 hours and met at least one of the following three criteria: ► a recognised pathogen (eg, Staphylococcus aureus and Candida species) in one peripheral blood culture (ie, not taken through CVC) that was not related to an infection at another site (eg, meningitis or skin abscess), ► a common skin commensal (eg, coagulase-negative Staphylococcus (CONS)) cultured from two or more peripheral blood cultures drawn on separate occasions, ► a common skin commensal (eg, CONS) isolated from one peripheral blood culture with a CVC tip culture growing >15 colony-forming units of a pure growth of the same organism.
    End point type
    Primary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis used is unknown
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: CR-BSI/1000 catheter days
        number (not applicable)
    6.8
    6.2
    No statistical analyses for this end point

    Secondary: Number of subjects with skin damage from IMP

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    End point title
    Number of subjects with skin damage from IMP
    End point description
    Any area of skin irritation, erythema, excoriation or breakdown that was in the distribution of contact with the investigational medicinal product, and brought to the attention of the research team, was reported as an adverse skin reaction caused by a study solution.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
    3
    2
    Statistical analysis title
    Difference in proportion between arms
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.677
    Method
    Fisher exact
    Confidence interval

    Secondary: Incidence of raised thyroid-stimulating hormone on screening

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    End point title
    Incidence of raised thyroid-stimulating hormone on screening
    End point description
    Thyroid-stimulating hormone (TSH) values from 8 to 15 mU/L trigger a request for a repeat sample, and if persistently >15 mU/L prompt a request for formal serum thyroid function tests. Any abnormal TSH levels on newborn screening card or subsequent serum sample were recorded.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: incidence of raised TSH
    0
    12
    Statistical analysis title
    Difference in proportion between arms
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Fisher exact
    Confidence interval

    Secondary: Incidence of raised thyroid-stimulating hormone

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    End point title
    Incidence of raised thyroid-stimulating hormone
    End point description
    Thyroid-stimulating hormone (TSH) values from 8 to 15 mU/L trigger a request for a repeat sample, and if persistently >15 mU/L prompt a request for formal serum thyroid function tests. Any abnormal TSH levels on newborn screening card or subsequent serum sample were recorded.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: incidence of raised TSH
    0
    10
    Statistical analysis title
    Difference in proportion between arms
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of subjects requiring thyroxine replacement therapy

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    End point title
    Number of subjects requiring thyroxine replacement therapy
    End point description
    Number of subjects treated with thyroxine replacement therapy on the advice of paediatric endocrinologists.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
    0
    8
    Statistical analysis title
    Difference number of subjects requiring thyroxine
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of subjects with confirmed LOS (non-CR-BSI)

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    End point title
    Number of subjects with confirmed LOS (non-CR-BSI)
    End point description
    Number of subjects with confirmed late-onset sepsis (non-CR-BSI). Defined as laboratory confirmed sepsis (positive blood or cerebral spinal fluid culture for a recognised pathogen) after 72 hours of age and not related to a CVC.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
        Confirmed LOS
    17
    26
        No confirmed LOS
    131
    130
    Statistical analysis title
    Differen in incidence of confirmed LOS
    Comparison groups
    POV IOD v CHX-IA
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.249
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of subjects with suspected sepsis

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    End point title
    Number of subjects with suspected sepsis
    End point description
    Defined as clinical signs of sepsis, for example, increased frequency of apnoea, tachycardia or temperature instability, with negative blood culture, and treated with ≥5 days antibiotics.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
        Suspected sepsis
    13
    12
        No suspected sepsis
    135
    144
    Statistical analysis title
    Difference in subjects with susupected sepsis
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.835
    Method
    Fisher exact
    Confidence interval

    Secondary: Courses of antibiotics per subject

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    End point title
    Courses of antibiotics per subject
    End point description
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: Courses of antibiotics per subject
        median (inter-quartile range (Q1-Q3))
    2 (2 to 4)
    3 (2 to 4)
    Statistical analysis title
    Difference in mean courses of antibiotic/patient
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.588
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Total days of antibiotics per subject

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    End point title
    Total days of antibiotics per subject
    End point description
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: days
        median (inter-quartile range (Q1-Q3))
    5 (2 to 12)
    5 (2 to 12)
    No statistical analyses for this end point

    Secondary: Number of blood cultures performed per subject

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    End point title
    Number of blood cultures performed per subject
    End point description
    Number of blood cultures performed per subject. Decisions to remove CVCs and to perform blood cultures were at the discretion of treating clinicians to determine the presence of sepsis. If the blood culture was positive a further blood culture was taken from a different peripheral site. A second blood culture was not taken if the first was negative.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: blood cultures
        arithmetic mean (inter-quartile range (Q1-Q3))
    3 (2 to 5)
    3 (2 to 5)
    Statistical analysis title
    Difference in blood cultures/subject
    Comparison groups
    POV IOD v CHX-IA
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.319
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Number of subjects with any respiratory support on day 28

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    End point title
    Number of subjects with any respiratory support on day 28
    End point description
    The number of subjects who were receiving any respiratory support on day 28
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
        Respiratory support on day 28
    77
    89
        No respiratory support on day 28
    71
    67
    Statistical analysis title
    Difference subjects on respiratory support day 28
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.42
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of subjects with oxygen at 36 weeks CGA

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    End point title
    Number of subjects with oxygen at 36 weeks CGA
    End point description
    The number of subjects who were being treated with supplemental oxygen at a corrected gestational age of 36 weeks
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
        Oxygen at 36 weeks CGA
    27
    47
        No oxygen at 36 weeks CGA
    141
    109
    Statistical analysis title
    Difference in subjects with oxygen at 36 weeks CGA
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.017
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of subjects with NEC ≥ Bell stage 2

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    End point title
    Number of subjects with NEC ≥ Bell stage 2
    End point description
    The number of subjects with necrotising enterocolitis ≥ Bell stage 2.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
        NEC ≥ Bell stage 2
    14
    15
        No NEC ≥ Bell stage 2
    134
    141
    Statistical analysis title
    Difference in subjects with NEC≥Bell stage 2
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of subjects with any ROP

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    End point title
    Number of subjects with any ROP
    End point description
    The number of sujects with any retinopathy of prematurity.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
        ROP
    31
    15
        No ROP
    117
    141
    Statistical analysis title
    Difference in subjects with any ROP
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.845
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of subjects with CRUSS IVH III/IV or PVL

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    End point title
    Number of subjects with CRUSS IVH III/IV or PVL
    End point description
    The number of subjects with intraventricular haemorrhage grade III/IV or periventricular leukomalacia as determined by cranial ultrasound scan.
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: subjects
        CRUSS IVH III/IV or PVL
    16
    22
        No CRUSS IVH III/IV or PVL
    132
    134
    Statistical analysis title
    Difference subjects with CRUSS IVH III/IV or PVL
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.488
    Method
    Fisher exact
    Confidence interval

    Secondary: Number of deaths prior to hospital discharge

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    End point title
    Number of deaths prior to hospital discharge
    End point description
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: deaths
        Dead
    15
    18
        Alive
    133
    138
    Statistical analysis title
    Difference in deaths
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.716
    Method
    Fisher exact
    Confidence interval

    Secondary: Duration of hospital stay

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    End point title
    Duration of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    >72 hours after birth and had a CVC in situ or removed within the previous 48 hours until death or discharge of subject.
    End point values
    CHX-IA POV IOD
    Number of subjects analysed
    148
    156
    Units: days
        median (inter-quartile range (Q1-Q3))
    59 (49 to 85)
    67 (46 to 90)
    Statistical analysis title
    Difference in duration of hospital stay
    Comparison groups
    CHX-IA v POV IOD
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.199
    Method
    t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded over 39 months with non-serious adverse events reported every 3 months and serious adverse events reported within 24 hours.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NA
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    POV IOD
    Reporting group description
    Subjects in the PI arm were randomised to be treated with povidone–iodine.

    Reporting group title
    CHX-IA
    Reporting group description
    Subjects in the CHX–IA arm were randomised to be treated with chlorhexidine gluconate/isopropyl alcohol/water solution.

    Serious adverse events
    POV IOD CHX-IA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 156 (11.54%)
    15 / 148 (10.14%)
         number of deaths (all causes)
    18
    15
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Death before hospital discharge
         subjects affected / exposed
    18 / 156 (11.54%)
    15 / 148 (10.14%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 15
         deaths causally related to treatment / all
    0 / 18
    0 / 15
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    POV IOD CHX-IA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 156 (1.28%)
    3 / 148 (2.03%)
    Skin and subcutaneous tissue disorders
    Skin reaction
         subjects affected / exposed
    2 / 156 (1.28%)
    3 / 148 (2.03%)
         occurrences all number
    2
    3

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29074717
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