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    Clinical Trial Results:
    A blinded randomised placebo-controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants

    Summary
    EudraCT number
    		 2014-003237-25
    Trial protocol
    		 GB  
    Global end of trial date
    05 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Sep 2018
    First version publication date
    28 Sep 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    POPPIV4.022.07.16
    Additional study identifiers
    ISRCTN number
    		 ISRCTN82342359
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EudraCT Number: 2014-003237-25
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    CTRG, Research Services, Joint Research Office, Churchill Hospital, Oxford, United Kingdom, OX3 7LE
    Public contact
    Ms Heather House, University of Oxford, +44 01865572224, heather.house@admin.ox.ac.uk
    Scientific contact
    Ms Heather House, University of Oxford, +44 01865572224, heather.house@admin.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To test whether administration of morphine reduces clinical pain scores (PIPP-R) compared with a placebo (inactive solution) 30 seconds after an eye examination to test for retinopathy of prematurity (ROP). To test whether administration of morphine reduces pain-related brain activity compared with a placebo (inactive solution) following a clinically-essential heel lance.
    Protection of trial subjects
    Clinical stability was assessed throughout the 48-hour trial period (24 hours before and after the clinical intervention). These measures were calculated from pulse oximetry recordings and requirement for respiratory support. Pulse oximetry data were monitored and downloaded to the data logging equipment for 24 hours before and 24 hours after the start of the clinical intervention. Throughout the 48-hour trial period, blood pressure was monitored 6 hourly and changes in respiratory support (including type of respiratory support modality and oxygen requirement) were recorded. Drug safety was assessed by measuring the number of occurrences of apnoea that required intervention using NeoPuff or ‘bag and mask’, or hypotension that required treatment with inotropes in the 24-hour period after drug administration. The DMC planned to review trial safety outcomes after every 25 patients had been randomised and safety data collected (i.e. n=25, 50, 75, 100 and 125). In addition, the Chief Investigator (or suitably trained delegate) was notified of every such occurrence. A formal sequential safety procedure was applied and presented to the DMC for occurrences of apnoea that required intervention using NeoPuff or ‘bag and mask’. We employed a stopping boundary using group sequential methods with a boundary agreed by the DMC and specified in the DMC Charter.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    31
    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

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment to the trial began on 16th September 2016 and the last participant was recruited on 17 November 2017.

    Pre-assignment
    Screening details
    		 No screening data was collected.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Morphine sulphate and placebo solutions were delivered to the pharmacy in 10ml glass amber bottles with tamper-evident caps and a pack ID label, and dispensed to the Neonatal Unit. The solutions were indistinguishable by colour, odour and flow. Enrolment and randomisation of participants to a pack ID was carried out by the research team, using a web-based facility. The research team, clinical team, outcome assessors, infants and parents were masked to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    The volume of the dose of 100μg/kg of placebo (of equivalent volume) was calculated using the infant’s working weight (the most recent weight documented in the infant’s medical notes and used by the clinical team on their current drug prescription chart) and administered orally or via a nasogastric tube approximately 60 minutes prior to the heel lance.

    Arm title
    		 Morphine sulphate
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine sulphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    The volume of the dose of 100μg/kg of morphine sulphate (of equivalent volume) was calculated using the infant’s working weight (the most recent weight documented in the infant’s medical notes and used by the clinical team on their current drug prescription chart) and administered orally or via a nasogastric tube approximately 60 minutes prior to the heel lance.

    Number of subjects in period 1
    		Placebo Morphine sulphate
    Started
    16
    15
    Completed
    15
    15
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Morphine sulphate
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Morphine sulphate Total
    Number of subjects
    		 16 15 31
    Age categorical
    Gestational age at birth (weeks)
    Units: Subjects
        < 28+0 weeks
    		 6 7 13
        28+0 weeks or greater
    		 9 8 17
        Not recorded
    		 1 0 1
    Age continuous
    Gestational age at birth (weeks)
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    		 28.6 (27.9 to 29.7) 28.1 (26.3 to 30.1) -
    Gender categorical
    Units: Subjects
        Female
    		 7 3 10
        Male
    		 8 12 20
        Not recorded
    		 1 0 1
    Gestational age at randomisation (weeks)
    Units: Subjects
        34+0 to 35+6 weeks
    		 12 14 26
        36+0 to 37+6 weeks
    		 2 0 2
        38+0 to 39+6 weeks
    		 1 1 2
        40+0 to 42+6 weeks
    		 0 0 0
        Not recorded
    		 1 0 1
    Mode of delivery
    Units: Subjects
        Spontaneous vaginal delivery
    		 5 8 13
        Assisted delivery
    		 0 0 0
        Caesarean section (elective or emergency)
    		 10 7 17
        Other
    		 0 0 0
        Not recorded
    		 1 0 1
    Days ventilated at randomisation
    Units: Subjects
        0 days
    		 3 9 12
        1 to < 7 days
    		 8 2 10
        7 or more days
    		 4 4 8
        Not recorded
    		 1 0 1
    Days since morphine was given
    Units: Subjects
        No morphine given
    		 8 11 19
        < 3 days
    		 0 0 0
        3 to < 7 days
    		 1 0 1
        7 or more days
    		 6 4 10
        Not recorded
    		 1 0 1
    Presence of gastric tube at randomisation
    Units: Subjects
        Yes
    		 15 14 29
        No
    		 0 1 1
        Not recorded
    		 1 0 1
    Intrauterine growth restriction
    Units: Subjects
        Yes
    		 3 2 5
        No
    		 12 13 25
        Not recorded
    		 1 0 1
    Baby has had surgery
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 14 15 29
        Not recorded
    		 1 0 1
    Intraventricular haemorrhage (IVH) Grade I/II
    Units: Subjects
        Yes
    		 3 2 5
        No
    		 12 13 25
        Not recorded
    		 1 0 1
    Baby is one of a multiple pregnancy
    Units: Subjects
        Yes
    		 4 4 8
        No
    		 11 11 22
        Not recorded
    		 1 0 1
    Conceived using IVF treatment
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 15 14 29
        Not recorded
    		 1 0 1
    Gestational age at randomisation (weeks)
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    		 34.7 (34.1 to 35.1) 34.7 (34.1 to 35.1) -
    Birth weight
    Units: Grams
        arithmetic mean (standard deviation)
    		 1173.4 ( 349.5 ) 1107.0 ( 328.7 ) -
    Birth weight z-score (adjusted for sex and gestational age at birth)
    Units: standard deviations
        arithmetic mean (standard deviation)
    		 -0.2 ( 1.0 ) -0.4 ( 0.9 ) -
    Weight at randomisation
    Units: Grams
        arithmetic mean (standard deviation)
    		 2130.7 ( 331.5 ) 2048.5 ( 425.9 ) -
    Apgar score at 10 minutes of age
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 10 (8 to 10) 10 (9 to 10) -
    Days ventilated at randomisation
    Units: Days
        median (inter-quartile range (Q1-Q3))
    		 3.5 (2.0 to 19.5) 8.0 (1.0 to 20.0) -
    Days since morphine was given
    Units: Days
        median (inter-quartile range (Q1-Q3))
    		 19.0 (15.0 to 39.0) 46.5 (33.5 to 49.0) -
    Subject analysis sets

    Subject analysis set title
    Per protocol population - Placebo arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population is infants randomised who received both the study treatment and the clinical intervention (heel lance followed by ROP screening), excluding post-randomisation exclusions. Baseline characteristics are reported for all infants randomised for whom data are available, excluding post-randomisation exclusions. The following will be excluded from the per-protocol analysis population post-randomisation: • Participants who did not receive the study treatment • Participants who did not receive the clinical intervention (heel lance followed by ROP screening) • Participants randomised in error • Participants for whom full consent was not obtained • Participants for whom consent to use their data was withdrawn by the parent(s) • Participants for whom an entire record of fraudulent data was detected. This group excludes the 1 baby for whom consent was withdrawn, who did not receive the treatment or clinical intervention.

    Subject analysis set title
    Per protocol population - Morphine arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population is infants randomised who received both the study treatment and the clinical intervention (heel lance followed by ROP screening), excluding post-randomisation exclusions. Baseline characteristics are reported for all infants randomised for whom data are available, excluding post-randomisation exclusions. The following will be excluded from the per-protocol analysis population post-randomisation: • Participants who did not receive the study treatment • Participants who did not receive the clinical intervention (heel lance followed by ROP screening) • Participants randomised in error • Participants for whom full consent was not obtained • Participants for whom consent to use their data was withdrawn by the parent(s) • Participants for whom an entire record of fraudulent data was detected. No babies were excluded from the morphine arm.

    Subject analysis sets values
    		 Per protocol population - Placebo arm Per protocol population - Morphine arm
    Number of subjects
    15
    15
    Age categorical
    Gestational age at birth (weeks)
    Units: Subjects
        < 28+0 weeks
    6
    7
        28+0 weeks or greater
    9
    8
        Not recorded
    0
    0
    Age continuous
    Gestational age at birth (weeks)
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    28.6 (27.9 to 29.7)
    28.1 (26.3 to 30.1)
    Gender categorical
    Units: Subjects
        Female
    7
    3
        Male
    8
    12
        Not recorded
    0
    0
    Gestational age at randomisation (weeks)
    Units: Subjects
        34+0 to 35+6 weeks
    12
    14
        36+0 to 37+6 weeks
    2
    0
        38+0 to 39+6 weeks
    1
    1
        40+0 to 42+6 weeks
    0
    0
        Not recorded
    0
    0
    Mode of delivery
    Units: Subjects
        Spontaneous vaginal delivery
    5
    8
        Assisted delivery
    0
    0
        Caesarean section (elective or emergency)
    10
    7
        Other
    0
    0
        Not recorded
    0
    0
    Days ventilated at randomisation
    Units: Subjects
        0 days
    3
    9
        1 to < 7 days
    8
    2
        7 or more days
    4
    4
        Not recorded
    0
    0
    Days since morphine was given
    Units: Subjects
        No morphine given
    8
    11
        < 3 days
    0
    0
        3 to < 7 days
    1
    0
        7 or more days
    6
    4
        Not recorded
    0
    0
    Presence of gastric tube at randomisation
    Units: Subjects
        Yes
    15
    14
        No
    0
    1
        Not recorded
    0
    0
    Intrauterine growth restriction
    Units: Subjects
        Yes
    3
    2
        No
    12
    13
        Not recorded
    0
    0
    Baby has had surgery
    Units: Subjects
        Yes
    1
    0
        No
    14
    15
        Not recorded
    0
    0
    Intraventricular haemorrhage (IVH) Grade I/II
    Units: Subjects
        Yes
    3
    2
        No
    12
    13
        Not recorded
    0
    0
    Baby is one of a multiple pregnancy
    Units: Subjects
        Yes
    4
    4
        No
    11
    11
        Not recorded
    0
    0
    Conceived using IVF treatment
    Units: Subjects
        Yes
    0
    1
        No
    15
    14
        Not recorded
    0
    0
    Gestational age at randomisation (weeks)
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    Birth weight
    Units: Grams
        arithmetic mean (standard deviation)
    ( )
    ( )
    Birth weight z-score (adjusted for sex and gestational age at birth)
    Units: standard deviations
        arithmetic mean (standard deviation)
    ( )
    ( )
    Weight at randomisation
    Units: Grams
        arithmetic mean (standard deviation)
    ( )
    ( )
    Apgar score at 10 minutes of age
    Units: Score
        median (inter-quartile range (Q1-Q3))
    Days ventilated at randomisation
    Units: Days
        median (inter-quartile range (Q1-Q3))
    Days since morphine was given
    Units: Days
        median (inter-quartile range (Q1-Q3))

    End points

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

    Reporting group title
    Morphine sulphate
    Reporting group description
    		 -

    Subject analysis set title
    Per protocol population - Placebo arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population is infants randomised who received both the study treatment and the clinical intervention (heel lance followed by ROP screening), excluding post-randomisation exclusions. Baseline characteristics are reported for all infants randomised for whom data are available, excluding post-randomisation exclusions. The following will be excluded from the per-protocol analysis population post-randomisation: • Participants who did not receive the study treatment • Participants who did not receive the clinical intervention (heel lance followed by ROP screening) • Participants randomised in error • Participants for whom full consent was not obtained • Participants for whom consent to use their data was withdrawn by the parent(s) • Participants for whom an entire record of fraudulent data was detected. This group excludes the 1 baby for whom consent was withdrawn, who did not receive the treatment or clinical intervention.

    Subject analysis set title
    Per protocol population - Morphine arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population is infants randomised who received both the study treatment and the clinical intervention (heel lance followed by ROP screening), excluding post-randomisation exclusions. Baseline characteristics are reported for all infants randomised for whom data are available, excluding post-randomisation exclusions. The following will be excluded from the per-protocol analysis population post-randomisation: • Participants who did not receive the study treatment • Participants who did not receive the clinical intervention (heel lance followed by ROP screening) • Participants randomised in error • Participants for whom full consent was not obtained • Participants for whom consent to use their data was withdrawn by the parent(s) • Participants for whom an entire record of fraudulent data was detected. No babies were excluded from the morphine arm.

    Primary: PIPP-R score 30 seconds after ROP screening

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    End point title
    		 PIPP-R score 30 seconds after ROP screening
    End point description
    End point type
    Primary
    End point timeframe
    30 seconds after ROP screening
    End point values
    		 Per protocol population - Placebo arm Per protocol population - Morphine arm
    Number of subjects analysed
    15
    15
    Units: Score
        arithmetic mean (standard deviation)
    10.5 ( 3.4 )
    11.1 ( 3.2 )
    Statistical analysis title
    		 Mean difference
    Statistical analysis description
    Unadjusted mean difference
    Comparison groups
    Per protocol population - Placebo arm v Per protocol population - Morphine arm
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6634
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 3

    Primary: Magnitude of nociceptive-specific brain activity evoked by heel lance

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    End point title
    		 Magnitude of nociceptive-specific brain activity evoked by heel lance
    End point description
    End point type
    Primary
    End point timeframe
    At heel lance (clinical intervention)
    End point values
    		 Per protocol population - Placebo arm Per protocol population - Morphine arm
    Number of subjects analysed
    14 [1]
    15
    Units: Projected weight of template
        median (inter-quartile range (Q1-Q3))
    0.75 (0.33 to 1.22)
    0.99 (0.40 to 1.56)
    Notes
    [1] - 1 missing
    Statistical analysis title
    		 Median difference
    Statistical analysis description
    Unadjusted median difference
    Comparison groups
    Per protocol population - Placebo arm v Per protocol population - Morphine arm
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2474
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.8

    Secondary: PIPP-R score following heel lance

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    End point title
    		 PIPP-R score following heel lance
    End point description
    End point type
    Secondary
    End point timeframe
    30 second period after heel lance
    End point values
    		 Per protocol population - Placebo arm Per protocol population - Morphine arm
    Number of subjects analysed
    15
    15
    Units: Score
        arithmetic mean (standard deviation)
    8.5 ( 3.9 )
    7.9 ( 3.4 )
    Statistical analysis title
    		 Mean difference
    Statistical analysis description
    Unadjusted mean difference
    Comparison groups
    Per protocol population - Placebo arm v Per protocol population - Morphine arm
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6571
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 2.1

    Secondary: Amplitude of reflex withdrawal following heel lance

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    End point title
    		 Amplitude of reflex withdrawal following heel lance
    End point description
    End point type
    Secondary
    End point timeframe
    After heel lance
    End point values
    		 Per protocol population - Placebo arm Per protocol population - Morphine arm
    Number of subjects analysed
    14 [2]
    15
    Units: RMS activity
        median (inter-quartile range (Q1-Q3))
    12.38 (6.11 to 46.33)
    24.84 (19.66 to 44.84)
    Notes
    [2] - 1 missing
    Statistical analysis title
    		 Median difference
    Statistical analysis description
    Unadjusted median difference
    Comparison groups
    Per protocol population - Placebo arm v Per protocol population - Morphine arm
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4849
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    8.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.01
         upper limit
    		 22.39

    Other pre-specified: Incidents of apnoea that require intervention using NeoPuff or ‘bag and mask’ in the 24-hour period following drug administration

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    End point title
    		 Incidents of apnoea that require intervention using NeoPuff or ‘bag and mask’ in the 24-hour period following drug administration
    End point description
    Safety outcome
    End point type
    Other pre-specified
    End point timeframe
    24-hour period following drug administration
    End point values
    		 Per protocol population - Placebo arm Per protocol population - Morphine arm
    Number of subjects analysed
    15
    15
    Units: Infants
        >= 1
    0
    3
        None
    15
    12
    Statistical analysis title
    		 Risk difference
    Statistical analysis description
    Unadjusted risk difference
    Comparison groups
    Per protocol population - Morphine arm v Per protocol population - Placebo arm
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0528
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.4

    Other pre-specified: Incidents of hypotension that require treatment with inotropes in the 24-hour period following drug administration

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    End point title
    		 Incidents of hypotension that require treatment with inotropes in the 24-hour period following drug administration
    End point description
    Safety outcome
    End point type
    Other pre-specified
    End point timeframe
    24-hour period following drug administration
    End point values
    		 Per protocol population - Placebo arm Per protocol population - Morphine arm
    Number of subjects analysed
    15
    15
    Units: Infants
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 hours after study treatment administered
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Not applicable
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Safety population - Placebo
    Reporting group description
    		 Safety analyses include all infants randomised who received the study treatment. In the placebo arm, one infant did not receive the study treatment and is excluded from this population.

    Reporting group title
    Safety population - Morphine
    Reporting group description
    		 Safety analyses includes all infants randomised who received the study treatment. In the morphine arm, all infants received the study treatment.

    Serious adverse events
    		 Safety population - Placebo Safety population - Morphine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Desaturations
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Safety population - Placebo Safety population - Morphine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
    8 / 15 (53.33%)
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Desaturations
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    Apnoea
         subjects affected / exposed
    0 / 15 (0.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    5
    Skin and subcutaneous tissue disorders
    Perineal rash
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0

    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.
    The trial was terminated early after the predefined safety stopping boundary was crossed. This means that a smaller number of subjects was analysed than planned, and the study was under-powered.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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