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    Clinical Trial Results:
    A Randomised Controlled Double-Blind Trial of Intranasal Fentanyl versus Intravenous Morphine in the Emergency Department Treatment of Severe Painful Sickle Cell Crises in Children

    Summary
    EudraCT number
    		 2011-005161-20
    Trial protocol
    		 IE  
    Global end of trial date
    14 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2019
    First version publication date
    28 Jul 2019
    Other versions
    Summary report(s)
    		 Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: study protocol for a randomised controlled trial

    Trial information

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    Trial identification
    Sponsor protocol code
    SCC01
    Additional study identifiers
    ISRCTN number
    		 ISRCTN67469672
    US NCT number
    		 NCT03682211
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Our Lady's Children's Hospital, Crumlin
    Sponsor organisation address
    Cooley Road, Dublin, Ireland,
    Public contact
    Dr Michael Barrett, Our Lady's Children's Hospital, Crumlin, 353 014096814,
    Scientific contact
    Dr Michael Barrett, Our Lady's Children's Hospital, Crumlin, 353 014096814,
    Sponsor organisation name
    University College Dublin
    Sponsor organisation address
    Belfield, Dublin, Ireland,
    Public contact
    Clinical Research Centre, University College Dublin, 353 17164582,
    Scientific contact
    Clinical Research Centre, University College Dublin, 353 17164582,
    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
    02 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to illustrate the comparative efficacy of intranasal fentanyl to IV morphine in reducing severe pain associated with Painful Sickle Cell Crises in the Emergency Department.
    Protection of trial subjects
    Informed written consent was obtained from parent(s) and age appropriate assent from each eligible patient attending the hospital's outpatient hemoglobinopathy service prior to patient recruitment in the ED. Each consented family and trial patient was provided with a Contact card so that trial personnel could be contacted about impending acute presentations. Verbal re-consent and assent were obtained at ED presentation. Harm and stress were minimised as per the clinical guidelines for this patient cohort in Our Lady's Children's Hosptial, Crumlin. Trial subjects were treated and monitored in the hospital accidents and emergencies unit where immediate care was available to minimise pain and distress.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ireland: 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
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    1
    Children (2-11 years)
    16
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Informed written consent was obtained from parent(s) and age-appropriate assent from each eligible patient attending the hospital’s outpatient hemoglobinopathy service prior to patient recruitment in the emergency department

    Pre-assignment
    Screening details
    		 Eligible patients were children and adolescents aged between 1 and 21 years with SCD consecutively presenting to the ED with acute severe pain. Severe pain was defined as pain due to SCD in the extremities, back, abdomen or chest that was rated 7 or greater on a 0–10 numeric pain scale or equivalent.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intravenous Morphine Group
    Arm description
    		 Trial Subjects were randomly assigned to receive 0.1mg/kg of intravenous Morphine with intranasal placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine Sulphate 10mg/ml BP
    Investigational medicinal product code
    Other name
    Morphine Sulphate
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single administration of Intravenous solution within 2 minutes after patient receives intranasal solution Dose was morphine calculated based on patient receiving an immediate dose of 0.1mg/kg. Intravenous preparation administered via an IV cannula.

    Investigational medicinal product name
    Water for injection
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Administration of intranasal solution first followed within 2 minutes by administration of the IV solution. The matched shape and size of the placebo is a 2ml water for injection glass ampule. Intranasal medications will be administered using the Mucosal Atomiser Device (MAD) with a 1ml syringe. 1ml dose administered to each nostril.

    Arm title
    		 Intranasal Fentanyl Group
    Arm description
    		 Trial Subjects were randomly assigned to receive 1.5mcg/kg intranasal Fentanyl and intravenous placebo (water for injection).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fentanyl Citrate 50 microgram/mL
    Investigational medicinal product code
    Other name
    Fentanyl Citrate
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intranasal use
    Dosage and administration details
    Administration of Intranasal solution first followed within 2 minutes by administration of IV solution. The volume of intranasal solution calculated is based on each patient receiving an immediate dose of 1.5mcg/kg of Fentanyl. Intranasal solution will be administered between both nostrils via Mucosal atomiser device (MAD) with a 1ml syringe.

    Investigational medicinal product name
    Water for Injection
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solvent for parenteral use
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of IV solution within 2 minutes after patient receives Intranasal solution. 1ml Water for Injection glass ampoule is matched placebo for Intravenous Morphine and volume is calculated based on patient receiving an immediate dose of 0.1mg/kg. Intravenous preparation administered via an IV cannula.

    Number of subjects in period 1
    		Intravenous Morphine Group Intranasal Fentanyl Group
    Started
    16
    15
    Completed
    16
    15
    Period 2
    Period 2 title
    Endpoint period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intravenous Morphine Group
    Arm description
    		 Trial Subjects were randomly assigned to receive 0.1mg/kg of intravenous Morphine with intranasal placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine Sulphate 10mg/ml BP
    Investigational medicinal product code
    Other name
    Morphine Sulphate
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single administration of Intravenous solution within 2 minutes after patient receives intranasal solution Dose was morphine calculated based on patient receiving an immediate dose of 0.1mg/kg. Intravenous preparation administered via an IV cannula.

    Investigational medicinal product name
    Water for injection
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Administration of intranasal solution first followed within 2 minutes by administration of the IV solution. The matched shape and size of the placebo is a 2ml water for injection glass ampule. Intranasal medications will be administered using the Mucosal Atomiser Device (MAD) with a 1ml syringe. 1ml dose administered to each nostril.

    Arm title
    		 Intranasal Fentanyl Group
    Arm description
    		 Trial Subjects were randomly assigned to receive 1.5mcg/kg intranasal Fentanyl and intravenous placebo (water for injection).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fentanyl Citrate 50 microgram/mL
    Investigational medicinal product code
    Other name
    Fentanyl Citrate
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intranasal use
    Dosage and administration details
    Administration of Intranasal solution first followed within 2 minutes by administration of IV solution. The volume of intranasal solution calculated is based on each patient receiving an immediate dose of 1.5mcg/kg of Fentanyl. Intranasal solution will be administered between both nostrils via Mucosal atomiser device (MAD) with a 1ml syringe.

    Investigational medicinal product name
    Water for Injection
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solvent for parenteral use
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of IV solution within 2 minutes after patient receives Intranasal solution. 1ml Water for Injection glass ampoule is matched placebo for Intravenous Morphine and volume is calculated based on patient receiving an immediate dose of 0.1mg/kg. Intravenous preparation administered via an IV cannula.

    Number of subjects in period 2
    		Intravenous Morphine Group Intranasal Fentanyl Group
    Started
    16
    15
    Completed
    16
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intravenous Morphine Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 0.1mg/kg of intravenous Morphine with intranasal placebo

    Reporting group title
    Intranasal Fentanyl Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 1.5mcg/kg intranasal Fentanyl and intravenous placebo (water for injection).

    Reporting group values
    		 Intravenous Morphine Group Intranasal Fentanyl Group Total
    Number of subjects
    		 16 15 31
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 11.7 (7.0 to 15.2) 9.1 (5.9 to 14.4) -
    Gender categorical
    Units: Subjects
        Female
    		 6 7 13
        Male
    		 10 8 18
    Hydroxycarbamide therapy
    Units: Subjects
        Yes
    		 8 5 13
        No
    		 8 10 18
    Administered pre-hospital analgesia
    Units: Subjects
        Yes
    		 15 14 29
        No
    		 1 1 2
    History of painful episodes
    Units: Subjects
        Yes
    		 16 15 31
    History of intravenous Morphine administration
    Units: Subjects
        Yes
    		 10 10 20
        No
    		 2 2 4
        Uncertain
    		 4 3 7
    History of intranasal Fentanyl administration
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 16 15 31
    Number of visits to the emergency department in the past year
    Units: Subjects
        Zero
    		 5 3 8
        1-3
    		 11 8 19
        4 or more
    		 0 4 4
    Sickle Cell Disease Type
    Units: Subjects
        HbSS
    		 15 14 29
        HbSD
    		 1 0 1
        HbSC
    		 0 1 1
    Pain assessment tool
    Units: Subjects
        Manchester Pain Tool
    		 13 12 25
        Face, Legs, Activity, Cry and Consolability scale
    		 3 3 6
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 40.3 ± 19.9 36.2 ± 16.9 -
    Pain Score
    Units: score
        arithmetic mean (standard deviation)
    		 8.38 ± 0.96 8.2 ± 1.26 -

    End points

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    End points reporting groups
    Reporting group title
    Intravenous Morphine Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 0.1mg/kg of intravenous Morphine with intranasal placebo

    Reporting group title
    Intranasal Fentanyl Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 1.5mcg/kg intranasal Fentanyl and intravenous placebo (water for injection).
    Reporting group title
    Intravenous Morphine Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 0.1mg/kg of intravenous Morphine with intranasal placebo

    Reporting group title
    Intranasal Fentanyl Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 1.5mcg/kg intranasal Fentanyl and intravenous placebo (water for injection).

    Primary: Pain score at 10 minutes

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    End point title
    		 Pain score at 10 minutes
    End point description
    End point type
    Primary
    End point timeframe
    Pain score will be measured 10 minutes after administration of study medication
    End point values
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Number of subjects analysed
    16
    15
    Units: score
        arithmetic mean (standard deviation)
    4.6 ± 1.55
    6.0 ± 1.75
    Statistical analysis title
    		 Difference in mean pain scores at 10 minutes
    Comparison groups
    Intravenous Morphine Group v Intranasal Fentanyl Group
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.41
         upper limit
    		 -0.39

    Secondary: Time to patient-reported first change in pain intensity

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    End point title
    		 Time to patient-reported first change in pain intensity
    End point description
    End point type
    Secondary
    End point timeframe
    During 120 minutes after intervention
    End point values
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Number of subjects analysed
    15
    14
    Units: minutes
        arithmetic mean (confidence interval 95%)
    26.00 (4.49 to 47.50)
    8.57 (5.93 to 11.20)
    No statistical analyses for this end point

    Secondary: Required rescue intravenous morphine

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    End point title
    		 Required rescue intravenous morphine
    End point description
    End point type
    Secondary
    End point timeframe
    During 120 minutes after intervention
    End point values
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Number of subjects analysed
    16
    15
    Units: subjects
        Required analgesia
    2
    0
    No statistical analyses for this end point

    Secondary: Time to patient-reported first change from severe to mild pain

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    End point title
    		 Time to patient-reported first change from severe to mild pain
    End point description
    End point type
    Secondary
    End point timeframe
    During 120 minutes after intervention
    End point values
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Number of subjects analysed
    8
    14
    Units: minutes
        arithmetic mean (confidence interval 95%)
    67.50 (20.21 to 114.79)
    36.78 (14.24 to 59.34)
    No statistical analyses for this end point

    Secondary: Time to patient-reported first change from severe to no pain

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    End point title
    		 Time to patient-reported first change from severe to no pain
    End point description
    End point type
    Secondary
    End point timeframe
    During 120 minutes after intervention
    End point values
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Number of subjects analysed
    3
    4
    Units: minutes
        arithmetic mean (confidence interval 95%)
    45.00 (-19.54 to 109.54)
    47.50 (-29.77 to 124.77)
    No statistical analyses for this end point

    Secondary: Required additional oral analgesic medications (not acetaminophen or ibuprofen)

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    End point title
    		 Required additional oral analgesic medications (not acetaminophen or ibuprofen)
    End point description
    End point type
    Secondary
    End point timeframe
    During 120 minutes after intervention
    End point values
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Number of subjects analysed
    16
    15
    Units: subjects
    7
    1
    No statistical analyses for this end point

    Secondary: Lowest depth of sedation

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    End point title
    		 Lowest depth of sedation
    End point description
    Lowest depth of sedation as reported by University of Michigan Sedation Scale Scores
    End point type
    Secondary
    End point timeframe
    During 120 minutes after intervention
    End point values
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Number of subjects analysed
    16
    15
    Units: subjects
        Score 0
    7
    12
        Score 1
    7
    3
        Score 2
    2
    0
        Score 3
    0
    0
        Score 4
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported for the duration of trial, 120 minutes post administration of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NA
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Intravenous Morphine Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 0.1mg/kg of intravenous Morphine with intranasal placebo

    Reporting group title
    Intranasal Fentanyl Group
    Reporting group description
    		 Trial Subjects were randomly assigned to receive 1.5mcg/kg intranasal Fentanyl and intravenous placebo (water for injection).

    Serious adverse events
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intravenous Morphine Group Intranasal Fentanyl Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 15 (6.67%)
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal discomfort
         subjects affected / exposed
    4 / 16 (25.00%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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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
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