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    Clinical Trial Results:
    Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen

    Summary
    EudraCT number
    		 2019-004297-26
    Trial protocol
    		 FR   EE   IE   FI   BE   PT   SE   HU   DK   GB   NO   AT   GR   PL   IT  
    Global end of trial date
    20 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions
    Summary report(s)
    		 SUMMARY_PROTOCOL

    Trial information

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    Trial identification
    Sponsor protocol code
    C19-29
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04459117
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inserm
    Sponsor organisation address
    8 rue de la Croix Jarry, Paris, France, 75013
    Public contact
    Sandrine COUFFIN-CADIERGUES, Inserm, 33 144 23 64 16, rqrc.siege@inserm.fr
    Scientific contact
    Sandrine COUFFIN-CADIERGUES, Inserm, 33 144 23 64 16, rqrc.siege@inserm.fr
    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
    13 Feb 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jun 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives : Phase II: The objective of Phase II is to define the minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7 in preterm infants of 23-26 weeks of gestation Phase III: The primary objective is an increase in surviving without severe morbidity at 36 weeks of post menstrual age (or at discharge if it occurs before) from 50% (placebo group) to 60% in group receiving a prophylactic treatment by acetaminophen during the first 5 days of life.
    Protection of trial subjects
    Adverse events—including serious adverse events, deaths, and events related to the underlying disease—are recorded and reported in accordance with the Safety Management Plan and applicable ICH-GCP/EU requirements. Independent oversight is ensured through the following bodies, which convene regularly: Inserm Pharmacovigilance, National Hub Pharmacovigilance Responsible Person (NH PVRP), Data and Safety Monitoring Board (DSMB), Trial Management Group (TMG), and Trial Steering Committee (TSC). Emergency code-break (unblinding) procedures are available and restricted to situations where knowledge of treatment allocation is essential for subject management; all instances are documented. Predefined criteria for treatment discontinuation are in place. For blood sampling, in Phase II up to six tubes per subject will be collected in line with routine clinical practice. In Phase III, two samples are taken during routine care; additional tubes will be collected in a subset of 50 patients only.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research, Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Portugal: 30
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Estonia: 33
    Country: Number of subjects enrolled
    Finland: 58
    Country: Number of subjects enrolled
    France: 457
    Country: Number of subjects enrolled
    Ireland: 19
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Switzerland: 85
    Country: Number of subjects enrolled
    Greece: 34
    Worldwide total number of subjects
    804
    EEA total number of subjects
    719
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    804
    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
    		 First inclusion on October, the 29th 2020. End of study on June, the 20th 2024. Database lock on January, the 15th 2025. Parents/guardians approached, written consent before randomisation. Central IWRS 1:1, acetaminophen vs placebo, stratified by Gestational Age and centre.

    Pre-assignment
    Screening details
    		 Screening in NICU within hours of birth. Inclusion: Birth between 23-26 W for Phase II, between 23-28 W for Phase III, Post natal age < 12 hours, Parental or Legal Authority Consent, Parents with a social security or health insurance. Exclusion: Birth defect/Congenital anomaly, Twin-to-twin transfusion syndrome not cured...

    Pre-assignment period milestones
    Number of subjects started
    		 804
    Number of subjects completed
    		 778

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 No parental authorisation: 1
    Reason: Number of subjects
    		 IMP not available in time: 6
    Reason: Number of subjects
    		 Clinical instability that can lead to rapid death: 2
    Reason: Number of subjects
    		 Suspicion of pulmonary hypoplasia: 1
    Reason: Number of subjects
    		 infants with congenital anomaly: 3
    Reason: Number of subjects
    		 Withdrawal before primary outcome: 4
    Reason: Number of subjects
    		 Missing Primary outcome: 5
    Reason: Number of subjects
    		 Impossibility to start IMP before 12h: 4
    Period 1
    Period 1 title
    Phase III - Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Polyethylene ampoule of 10ml of NaCL 0.9%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Phase II : The first level will be 20 mg/kg loading dose within 12 hours after birth followed by 7.5 mg/kg/ 6 hours during 5 days (total = 20 doses). The 2nd, 3rd and 4th level doses will stand for 25%, 50%, and 75% increase of the first level: - 25 mg/kg loading dose within 12 hours after birth followed by 10 mg/kg/ 6 hours during 5 days (total = 20 doses) - 30 mg/kg loading dose within 12 hours after birth followed by 12 mg/kg/ 6 hours during 5 days (total = 20 doses) - 35 mg/kg loading dose within 12 hours after birth followed by 15 mg/kg/ 6 hours during 5 days (total = 20 doses) Phase III: - In the 27-28 weeks gestational age group, the dosage is 20 mg/kg loading dose within 12 hours after birth followed by 7.5 mg/kg/ 6 hours (+/-15min) during 5 days (total = 20 doses). - In the 23-26 weeks gestational age group, the dosage will be minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7, found during the phase II.

    Arm title
    		 Investigational Medicinal Product
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Acetaminophen 100 mg per 10 mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the 27-28 weeks gestational age group, the dosage is 20 mg/kg loading dose within 12 hours after birth followed by 7.5 mg/kg/ 6 hours (+/- 15 min) during 5 days (total = 20 doses). o In the 23-26 weeks gestational age group, the dosage will be minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7, found during the phase II.

    Number of subjects in period 1 [1]
    		Placebo Investigational Medicinal Product
    Started
    387
    391
    Completed
    387
    391
    Notes
    [1] - 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: The baseline period counts only subjects who started Phase III treatment (Modified intention-to-treat (mITT) N=778). The ‘worldwide number enrolled’ (804) includes consented but not randomised infants, therefore totals differ.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase III - Treatment
    Reporting group description
    		 Modified intention-to-treat (mITT) analysis set: 778 infants (acetaminophen n=391; placebo n=387).

    Reporting group values
    		 Phase III - Treatment Total
    Number of subjects
    		 778 778
    Age categorical
    Units: Subjects
        23 weeks
    		 23 23
        24 weeks
    		 85 85
        25 weeks
    		 119 119
        26 weeks
    		 173 173
        27 weeks
    		 186 186
        28 weeks
    		 192 192
    Gender categorical
    Units: Subjects
        Female
    		 375 375
        Male
    		 403 403
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set – Phase III (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised infants in Phase III, analysed as assigned (intention-to-treat). Baseline characteristics are those collected at/just before randomisation. Phase II dose-finding subjects are not included in this analysis set.

    Subject analysis sets values
    		 Full Analysis Set – Phase III (ITT)
    Number of subjects
    778
    Age categorical
    Units: Subjects
        23 weeks
    23
        24 weeks
    85
        25 weeks
    119
        26 weeks
    173
        27 weeks
    186
        28 weeks
    192
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    375
        Male
    403

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Investigational Medicinal Product
    Reporting group description
    		 -

    Subject analysis set title
    Full Analysis Set – Phase III (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised infants in Phase III, analysed as assigned (intention-to-treat). Baseline characteristics are those collected at/just before randomisation. Phase II dose-finding subjects are not included in this analysis set.

    Primary: Death or severe morbidity at 36 wk of postmenstrual age

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    End point title
    		 Death or severe morbidity at 36 wk of postmenstrual age
    End point description
    End point type
    Primary
    End point timeframe
    at 36 wk of postmenstrual age
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    387
    391
    Units: Participants
        Death
    57
    48
        Survival with severe bronchopulmonary dysplasia
    40
    44
        Intraventricular hemorrhage Grade III or IV
    45
    40
        Cystic periventricular leukomalacia
    17
    20
        Severe necrotizing enterocolitis
    43
    34
    Statistical analysis title
    		 Primary analysis - modified ITT
    Statistical analysis description
    Two-arm superiority comparison (paracetamol vs placebo) on survival without severe morbidity at 36 weeks PMA. Analysis set: modified ITT. Group-sequential O’Brien–Fleming design with interim looks at N=397 and N=595 (z-bounds ±2.86; ±2.34) and final bound ±2.02 at N≈793. Effect measure: risk ratio with two-sided 95% CI; α=0.05 overall. Test based on Z statistic for a binary endpoint (final p-value from normalized Z). Missing data: complete-case (no imputation)
    Comparison groups
    Placebo v Investigational Medicinal Product
    Number of subjects included in analysis
    778
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.16

    Secondary: Pulmonary hemorrhage (before day8)

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    End point title
    		 Pulmonary hemorrhage (before day8)
    End point description
    End point type
    Secondary
    End point timeframe
    Before day 8
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    387
    391
    Units: Participants
    20
    15
    No statistical analyses for this end point

    Secondary: Number of days with enteral feeding during first week

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    End point title
    		 Number of days with enteral feeding during first week
    End point description
    End point type
    Secondary
    End point timeframe
    at 7 days of postnatal age
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    387
    391
    Units: day
        median (inter-quartile range (Q1-Q3))
    8 (6 to 8)
    8 (7 to 8)
    No statistical analyses for this end point

    Secondary: Median volume of enteral nutrition at day 7, ml/kg, (IQR)

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    End point title
    		 Median volume of enteral nutrition at day 7, ml/kg, (IQR)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 7 of life
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    365
    369
    Units: ml/kg
        median (inter-quartile range (Q1-Q3))
    65 (22 to 112)
    64 (22.5 to 112)
    No statistical analyses for this end point

    Secondary: Median maximal Weight loss during first week after birth

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    End point title
    		 Median maximal Weight loss during first week after birth
    End point description
    End point type
    Secondary
    End point timeframe
    First 7 days after birth.
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    387
    390
    Units: % (of birth weight)
        median (inter-quartile range (Q1-Q3))
    8.08 (4.14 to 11.36)
    5.5 (2.51 to 8.91)
    No statistical analyses for this end point

    Secondary: Respiratory support at day 7

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    End point title
    		 Respiratory support at day 7
    End point description
    End point type
    Secondary
    End point timeframe
    Day 7 of life.
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    367
    370
    Units: Participants
        No support
    13
    19
        Noninvasive respiratory support
    241
    257
        Invasive respiratory support
    113
    94
    No statistical analyses for this end point

    Secondary: At least one catecholamine support

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    End point title
    		 At least one catecholamine support
    End point description
    End point type
    Secondary
    End point timeframe
    Birth to day 7 inclusive.
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    387
    391
    Units: Participants
    89
    79
    No statistical analyses for this end point

    Secondary: At least one sedation/analgesia

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    End point title
    		 At least one sedation/analgesia
    End point description
    End point type
    Secondary
    End point timeframe
    Birth to day 7 inclusive.
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    387
    391
    Units: Participants
    159
    159
    No statistical analyses for this end point

    Secondary: At least one steroid

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    End point title
    		 At least one steroid
    End point description
    End point type
    Secondary
    End point timeframe
    Birth to day 7 inclusive.
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    387
    391
    Units: Participants
    134
    117
    No statistical analyses for this end point

    Secondary: Any retinopathy of prematurity (ROP)

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    End point title
    		 Any retinopathy of prematurity (ROP)
    End point description
    End point type
    Secondary
    End point timeframe
    at 36 weeks of postmenstrual age
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    310
    322
    Units: Participants
    132
    131
    No statistical analyses for this end point

    Secondary: Retinopathy of prematurity in at least one eye requiring treatment

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    End point title
    		 Retinopathy of prematurity in at least one eye requiring treatment
    End point description
    End point type
    Secondary
    End point timeframe
    at 36 weeks of postmenstrual age
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    310
    322
    Units: Participants
    19
    18
    No statistical analyses for this end point

    Secondary: Survival with any ventilatory support at 36 weeks PMA

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    End point title
    		 Survival with any ventilatory support at 36 weeks PMA
    End point description
    End point type
    Secondary
    End point timeframe
    at 36 weeks of postmenstrual age
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    330
    343
    Units: Participants
    169
    177
    No statistical analyses for this end point

    Secondary: Weight gain measured by change in z score

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    End point title
    		 Weight gain measured by change in z score
    End point description
    End point type
    Secondary
    End point timeframe
    at 36 weeks of postmenstrual age
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    361
    371
    Units: z score
        arithmetic mean (standard deviation)
    -0.73 ( 0.84 )
    -0.79 ( 0.84 )
    No statistical analyses for this end point

    Secondary: Head circumference gain measured by change in z score

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    End point title
    		 Head circumference gain measured by change in z score
    End point description
    End point type
    Secondary
    End point timeframe
    at 36 weeks of postmenstrual age
    End point values
    		 Placebo Investigational Medicinal Product
    Number of subjects analysed
    311
    318
    Units: z score
        arithmetic mean (standard deviation)
    0.14 ( 2.75 )
    0.08 ( 2.69 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 29-10-2020 (first inclusion) to 15-01-2025 (database lock)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28.0
    Reporting groups
    Reporting group title
    Acetaminophen phase II
    Reporting group description
    		 The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN.

    Reporting group title
    Acetaminophen phase III
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 The placebo product is a polyethylene ampoule of 10ml of NaCL 0.9%, B BRAUN. Polyethylene ampoule of active and placebo products are with the same appearance, in accordance with Good Manufacturing Practices Drugs for Clinical Trials.

    Serious adverse events
    		 Acetaminophen phase II Acetaminophen phase III Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 31 (41.94%)
    121 / 396 (30.56%)
    114 / 387 (29.46%)
         number of deaths (all causes)
    4
    51
    59
         number of deaths resulting from adverse events
    4
    51
    59
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vein thrombosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 31 (3.23%)
    8 / 396 (2.02%)
    9 / 387 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 6
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Emphysema
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 31 (0.00%)
    7 / 396 (1.77%)
    6 / 387 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 4
    0 / 4
    Laryngeal cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neonatal respiratory distress syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 31 (0.00%)
    7 / 396 (1.77%)
    6 / 387 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    5 / 396 (1.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    9 / 387 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 4
    Pulmonary hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    10 / 396 (2.53%)
    9 / 387 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    Respiratory acidosis
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 396 (0.25%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 396 (1.01%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Tracheomalacia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    3 / 387 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital diaphragmatic hernia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital small intestinal atresia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal atresia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Newborn persistent pulmonary hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patent ductus arteriosus
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypoplasia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sickle cell disease
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 396 (0.76%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    Pericardial effusion
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic cerebral infarction
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 31 (3.23%)
    16 / 396 (4.04%)
    9 / 387 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 16
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    1 / 12
    0 / 7
    Nervous system cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periventricular leukomalacia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Posthaemorrhagic hydrocephalus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Thrombocytosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    3 / 31 (9.68%)
    13 / 396 (3.28%)
    8 / 387 (2.07%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 14
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ascites
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stenosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meconium ileus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising enterocolitis neonatal
         subjects affected / exposed
    4 / 31 (12.90%)
    31 / 396 (7.83%)
    40 / 387 (10.34%)
         occurrences causally related to treatment / all
    0 / 4
    4 / 31
    0 / 41
         deaths causally related to treatment / all
    0 / 1
    2 / 10
    0 / 11
    Neonatal intestinal obstruction
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 396 (0.76%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcapsular hepatic haematoma
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 396 (0.51%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    4 / 387 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular disorder
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal vein thrombosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    1 / 31 (3.23%)
    11 / 396 (2.78%)
    12 / 387 (3.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    1 / 6
    0 / 8
    Candida sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis neonatal
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Enterococcal sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    6 / 387 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Serratia sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Systemic mycosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 396 (1.01%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 396 (0.00%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    4 / 387 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Acetaminophen phase II Acetaminophen phase III Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 31 (41.94%)
    152 / 396 (38.38%)
    145 / 387 (37.47%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of liver
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 31 (0.00%)
    4 / 396 (1.01%)
    2 / 387 (0.52%)
         occurrences all number
    0
    4
    2
    Hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Extravasation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Face oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Hypothermia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    3 / 387 (0.78%)
         occurrences all number
    0
    1
    3
    Chronic respiratory disease
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    2 / 387 (0.52%)
         occurrences all number
    0
    1
    2
    Epiglottic cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumothorax
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    4 / 387 (1.03%)
         occurrences all number
    0
    2
    4
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 31 (3.23%)
    6 / 396 (1.52%)
    2 / 387 (0.52%)
         occurrences all number
    1
    8
    2
    Pulmonary artery stenosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    9 / 396 (2.27%)
    8 / 387 (2.07%)
         occurrences all number
    0
    9
    8
    Pulmonary interstitial emphysema syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    1 / 387 (0.26%)
         occurrences all number
    0
    2
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Respiratory acidosis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    0 / 387 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Analgesic drug level above therapeutic
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    7 / 387 (1.81%)
         occurrences all number
    0
    3
    7
    Blood urea increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Blood lactic acid increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Ultrasound liver abnormal
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Cerebellar hypoplasia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital choroid plexus cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Endocardial fibroelastosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Epidermolysis bullosa
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Patent ductus arteriosus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    3 / 387 (0.78%)
         occurrences all number
    0
    1
    4
    Pulmonary artery stenosis congenital
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Re-opening of ductus arteriosus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    2
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary valve stenosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Cerebellar haematoma
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    0 / 387 (0.00%)
         occurrences all number
    1
    0
    0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Cerebral disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    3 / 387 (0.78%)
         occurrences all number
    0
    3
    3
    Lenticulostriatal vasculopathy
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences all number
    0
    2
    0
    Monoplegia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Neonatal seizure
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Periventricular leukomalacia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Seizure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    1
    0
    1
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Transverse sinus thrombosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    3 / 387 (0.78%)
         occurrences all number
    0
    0
    4
    Erythroblastosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    2 / 387 (0.52%)
         occurrences all number
    0
    0
    2
    Leukocytosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences all number
    0
    2
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Neutropenia
         subjects affected / exposed
    0 / 31 (0.00%)
    6 / 396 (1.52%)
    4 / 387 (1.03%)
         occurrences all number
    0
    6
    4
    Nucleated red cells
         subjects affected / exposed
    0 / 31 (0.00%)
    4 / 396 (1.01%)
    2 / 387 (0.52%)
         occurrences all number
    0
    4
    3
    Sickle cell anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 31 (6.45%)
    30 / 396 (7.58%)
    25 / 387 (6.46%)
         occurrences all number
    2
    32
    27
    Thrombocytosis
         subjects affected / exposed
    1 / 31 (3.23%)
    8 / 396 (2.02%)
    12 / 387 (3.10%)
         occurrences all number
    1
    9
    13
    Eye disorders
    Retinopathy of prematurity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Enterocolitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Food protein-induced enteropathy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Haematochezia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Inguinal hernia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    1
    0
    1
    Melaena
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Necrotising enterocolitis neonatal
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    2 / 387 (0.52%)
         occurrences all number
    0
    3
    2
    Neonatal intestinal obstruction
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophageal perforation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    16 / 396 (4.04%)
    20 / 387 (5.17%)
         occurrences all number
    0
    17
    23
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 31 (0.00%)
    22 / 396 (5.56%)
    9 / 387 (2.33%)
         occurrences all number
    0
    22
    10
    Hydrocholecystis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 31 (3.23%)
    14 / 396 (3.54%)
    7 / 387 (1.81%)
         occurrences all number
    1
    14
    7
    Anuria
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    2 / 387 (0.52%)
         occurrences all number
    0
    3
    2
    Nephrocalcinosis
         subjects affected / exposed
    0 / 31 (0.00%)
    4 / 396 (1.01%)
    3 / 387 (0.78%)
         occurrences all number
    0
    4
    3
    Oliguria
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    4 / 387 (1.03%)
         occurrences all number
    0
    3
    4
    Renal failure
         subjects affected / exposed
    1 / 31 (3.23%)
    10 / 396 (2.53%)
    8 / 387 (2.07%)
         occurrences all number
    1
    10
    8
    Renal tubular disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Central hypothyroidism
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperparathyroidism
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    0 / 387 (0.00%)
         occurrences all number
    0
    2
    0
    Immune-mediated hypothyroidism
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Osteomalacia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bacillus infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Candida infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Enterovirus infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Escherichia infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Escherichia sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Meningitis bacterial
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Blood potassium increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Carbohydrate intolerance
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Cell death
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    1
    1
    1
    Hyperferritinaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    0 / 387 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    4 / 31 (12.90%)
    15 / 396 (3.79%)
    19 / 387 (4.91%)
         occurrences all number
    8
    15
    22
    Hyperkalaemia
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 396 (1.01%)
    3 / 387 (0.78%)
         occurrences all number
    2
    4
    3
    Hypernatraemia
         subjects affected / exposed
    3 / 31 (9.68%)
    23 / 396 (5.81%)
    25 / 387 (6.46%)
         occurrences all number
    3
    23
    25
    Hyperphosphataemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    3 / 387 (0.78%)
         occurrences all number
    0
    1
    3
    Hypocalcaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 396 (0.76%)
    1 / 387 (0.26%)
         occurrences all number
    0
    3
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    5 / 396 (1.26%)
    3 / 387 (0.78%)
         occurrences all number
    0
    5
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    3 / 387 (0.78%)
         occurrences all number
    0
    1
    3
    Hyponatraemia
         subjects affected / exposed
    1 / 31 (3.23%)
    5 / 396 (1.26%)
    3 / 387 (0.78%)
         occurrences all number
    1
    5
    3
    Hypophosphataemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 396 (0.25%)
    1 / 387 (0.26%)
         occurrences all number
    0
    1
    1
    Lactic acidosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 396 (0.00%)
    1 / 387 (0.26%)
         occurrences all number
    0
    0
    1
    Metabolic acidosis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 396 (0.51%)
    4 / 387 (1.03%)
         occurrences all number
    0
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2020
    On 12 Feb 2021, recruitment was paused after an alert of 4 gastrointestinal perforations among 21 participants. The DSMB met on 16 Feb 2021 and, after reviewing all available data, found no evidence of a causal relationship with paracetamol (no imbalance between arms). Given that the rate of intestinal perforation in the cohort appeared higher than expected (acknowledging the small sample size), the DSMB recommended enhanced monitoring of intestinal complications and continuation of the trial. On 25 Feb 2021, the Trial Steering Committee implemented these safety recommendations by introducing closer surveillance: necrotising enterocolitis (NEC) and focal intestinal perforation were reclassified as ‘Other notable events’ and made subject to 24-hour reporting to the Pharmacovigilance Team to enable real-time review. No changes were made to the study objectives, primary endpoint or randomisation.
    31 Jan 2022
    Following a Swiss authority inspection, the protocol was clarified for AE reporting and concomitant medication reporting. Sections were updated and a new Appendix 20.9 (AE reporting tool) was added as requested by Switzerland. We also incorporated prior country-specific requests and editorial clarifications to harmonise versions. No changes to objectives, endpoints, randomisation, IMP or sample size.
    22 Nov 2022
    Update to harmonise protocol across countries. (1) Recruitment window extended from 28 to 42 months to reach target N; associated milestones updated (primary endpoint observation ends July 2024; last patient last visit July 2024; final monitoring Nov 2024). (2) Rescue treatment for PDA: criteria clarified per McNamara staging (C4/E3 or C3/E4 combination); recommendation wording aligned to allow local practice. (3) Disease-related events: list expanded to include all retinopathies (not only retinal surgery) recorded in the eCRF; no immediate SAE form required unless specified.
    22 Nov 2023
    This global operational amendment clarifies timing and data handling in busy neonatal intensive care units. IMP administration: a ±15-minute administration window is introduced to reflect real-life NICU conditions; a minimum interval of 5 hours 30 minutes between two administrations is specified. Both are compatible with the pharmacokinetic model and supported by the SmPC for paracetamol 10 mg/mL solution for infusion (B. Braun, 07/2022). Assessments: for Visit 3, a ±1-week window is defined for anthropometric measurements (head circumference, length, weight) to align with routine practice in which these are typically recorded weekly. Transfers between hospitals: the protocol now recognises standard-of-care transfers from tertiary NICUs to level IIA/IIB units and adds a new paragraph referring to a dedicated procedure. This standardises the process and clarifies responsibilities when a participant is transferred before completing participation: the receiving hospital must transmit Visit 2 and Visit 3 assessments and all safety data to the recruiting investigational site within the specified timelines and using agreed communication routes. Impact: these changes harmonise operations and ensure data completeness. There is no change to study objectives, endpoints, randomisation scheme, IMP composition/dose, or overall subject burden beyond the defined windows.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Mar 2021
    Based on the unexpectedly high incidence of gastrointestinal perforation, the sponsor decided on the following precautionary measures: - Convening the DSMB as soon as possible for an extraordinary meeting; the DSMB met on 16/02/2021 - Informing the investigating sites to suspend new enrolments. - Inform the trial steering committee in order to implement future recommendations published by the DSMB - Temporary suspension of the study
    12 Mar 2021

    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/39948605
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