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    Clinical Trial Results:
    The NAPRESSIM trial. The use of low dose prophylactic naloxone infusion to prevent respiratory depression with intrathecal morphine.

    Summary
    EudraCT number
    		 2015-003504-22
    Trial protocol
    		 IE  
    Global end of trial date
    06 Dec 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Jul 2020
    First version publication date
    29 Dec 2018
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    I would like to set the status of this record to 'draft' to be able to download the XML file of the results. This is not possible when the record is finalised. Please EMA Service Desk ticket #SD-247536 for more information. The ability to download the XML file of finalised results would be a very useful function.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UCDCRC/015/006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02885948
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College Dublin
    Sponsor organisation address
    Belfield, Dublin, Ireland,
    Public contact
    Clinical Research Centre, University College Dublin, +353 017164593, rabia.hussain@ucd.ie
    Scientific contact
    Clinical Research Centre, UCD Clinical Research Centre, +44 7496459789, davidcosgrave9@hotmail.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A reduction in the incidence of respiratory depression in patients who have received intrathecal morphine as part of their analgesic regimen for major hepatobiliary surgery.
    Protection of trial subjects
    All patients were cared for in a high dependency setting with 1:1 or 1:2 nursing care at all times. The clinical staff caring for the patients were allowed to institute whatever treatment including stopping the study infusion if they deemed it necessary. All protocol deviations were recorded.
    Background therapy
    		 All enrolled patients were undergoing major open hepatopancreaticobiliary surgery. Part of their analgesic regimen included administration of intrathecal morphine 10mcg/kg prior to induction.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    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: 95
    Worldwide total number of subjects
    95
    EEA total number of subjects
    95
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    74
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place from the 20th April 2016 to the 06th December 2017 . Two sites were involved, on one campus. St Vincent's University Hospital, Dublin, Ireland. St. Vincent's Private Hospital, Dublin, Ireland.

    Pre-assignment
    Screening details
    		 Inclusion: -Aged 18 or above -Eligible surgical procedure -Able to consent  Exclusion: -Allergy to naloxone -Pregnant or breast-feeding -Recent other investigational agent -Anticonvulsant medication -cardiac arrhythmia -chronic opioid use -contraindication to intrathecal injection -history of sleep apnoea -clinician preference

    Pre-assignment period milestones
    Number of subjects started
    		 225 [1]
    Number of subjects completed
    		 95

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Met Exclusion criteria: 22
    Reason: Number of subjects
    		 Clinician preference not to randomise: 87
    Reason: Number of subjects
    		 Eligible but didnt consent: 12
    Reason: Number of subjects
    		 Eligible but logistical reasons not to randomise: 6
    Reason: Number of subjects
    		 Randomised, surgery postponed, re-randomised: 1
    Reason: Number of subjects
    		 Didn't meet inclusion criteria: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The pre-assignment period contains all candidates screened for the trial. This is a much larger number than subjects recruited to the trial itself.
    Period 1
    Period 1 title
    Baseline Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Treating clinicians, investigators and patients were unaware of the subject allocation •The study pharmacist prepared the study infusion based on the randomisation code •Both the placebo and active infusion were clear colourless solutions, prepared in identical packaging •Labelling of infusions was identical •The treating physician, investigators, patients and other clinical staff had no access to the randomisation schedule

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Naloxone
    Arm description
    		 Patients in this arm of the study will receive an infusion of naloxone at a rate of 5mcg/kg/hr from within one hour of extubation post operatively, until 08.00 the first postoperative morning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxone hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10000mcg naloxone diluted to 500mls with 0.9% Sodium CHloride, to give a concentration of naloxone 20mcg/ml. This was infused at a rate of 0.25ml/kg/hr for the duration of the study period.

    Arm title
    		 Placebo
    Arm description
    		 Patients in this arm received 0.9% Sodium Chloride via intravenous infusion at a rate of 0.25ml/kg/hr from within one hour of extubation postoperatively, until 08.00 the first postoperative morning.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% Sodium CHloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The solution was administered at a rate of 0.25ml/kg/hr for the duration of the study period.

    Number of subjects in period 1
    		Naloxone Placebo
    Started
    48
    47
    Completed
    44
    43
    Not completed
    4
    4
         Protocol deviation
    4
    4
    Period 2
    Period 2 title
    Trial Period
    Is this the baseline period?
    		 No
    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
    		 Naloxone
    Arm description
    		 Patients in this arm of the study will receive an infusion of naloxone at a rate of 5mcg/kg/hr from within one hour of extubation post operatively, until 08.00 the first postoperative morning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxone hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10000mcg naloxone diluted to 500mls with 0.9% Sodium CHloride, to give a concentration of naloxone 20mcg/ml. This was infused at a rate of 0.25ml/kg/hr for the duration of the study period.

    Arm title
    		 Placebo
    Arm description
    		 Patients in this arm received 0.9% Sodium Chloride via intravenous infusion at a rate of 0.25ml/kg/hr from within one hour of extubation postoperatively, until 08.00 the first postoperative morning.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% Sodium CHloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The solution was administered at a rate of 0.25ml/kg/hr for the duration of the study period.

    Number of subjects in period 2
    		Naloxone Placebo
    Started
    44
    43
    Completed
    44
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Naloxone
    Reporting group description
    		 Patients in this arm of the study will receive an infusion of naloxone at a rate of 5mcg/kg/hr from within one hour of extubation post operatively, until 08.00 the first postoperative morning.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received 0.9% Sodium Chloride via intravenous infusion at a rate of 0.25ml/kg/hr from within one hour of extubation postoperatively, until 08.00 the first postoperative morning.

    Reporting group values
    		 Naloxone Placebo Total
    Number of subjects
    		 48 47 95
    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
        arithmetic mean (standard deviation)
    		 57.3 ± 11.1 54.8 ± 10.2 -
    Gender categorical
    Units: Subjects
        Female
    		 17 21 38
        Male
    		 31 26 57
    ASA Score
    American Society of Anesthesiologists Score: Baseline health / functional status scoring system.
    Units: Subjects
        ASA 1
    		 3 5 8
        ASA 2
    		 40 39 79
        ASA 3
    		 4 3 7
        Missing data
    		 1 0 1
    Type of Surgery
    All surgical procedures were major open hepatopancreaticobiliary procedures.
    Units: Subjects
        Whipples Procedure
    		 20 24 44
        Liver resection
    		 21 16 37
        Distal Pancreatectomy
    		 3 1 4
        Pancreatectomy
    		 0 1 1
        Other
    		 4 5 9
    BMI
    Body Mass Index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 26.9 ± 3.1 26.0 ± 4.4 -

    End points

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    End points reporting groups
    Reporting group title
    Naloxone
    Reporting group description
    		 Patients in this arm of the study will receive an infusion of naloxone at a rate of 5mcg/kg/hr from within one hour of extubation post operatively, until 08.00 the first postoperative morning.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received 0.9% Sodium Chloride via intravenous infusion at a rate of 0.25ml/kg/hr from within one hour of extubation postoperatively, until 08.00 the first postoperative morning.
    Reporting group title
    Naloxone
    Reporting group description
    		 Patients in this arm of the study will receive an infusion of naloxone at a rate of 5mcg/kg/hr from within one hour of extubation post operatively, until 08.00 the first postoperative morning.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received 0.9% Sodium Chloride via intravenous infusion at a rate of 0.25ml/kg/hr from within one hour of extubation postoperatively, until 08.00 the first postoperative morning.

    Subject analysis set title
    RespiratoryMotion ExSpiron Xi diagnosis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who were monitored for respiratory depression using the RespiratoryMotion ExSpiron Xi

    Subject analysis set title
    Clinical observations diagnosis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Clinical diagnosis of respiratory depression for Subjects who were monitored for respiratory depression using the Exspiron respiratory monitor.

    Subject analysis set title
    PaCO2 >6.6kPa RD Diagnosis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Diagnosis of respiratory depression by PaCO2 > 6.6kPa in patients who were monitored for respiratory depression using the Exspiron respiratory monitor

    Primary: Rate of respiratory depression in patients receiving naloxone infusion versus placebo

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    End point title
    		 Rate of respiratory depression in patients receiving naloxone infusion versus placebo
    End point description
    End point type
    Primary
    End point timeframe
    16-20 hours post administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: subjects
        Respiratory depression
    10
    21
        No respiratory depression
    34
    22
    Statistical analysis title
    		 Respiratory depression
    Statistical analysis description
    A one sided z test for independent proportions was used.
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0102
    Method
    		 z test for independent proportions
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.87

    Secondary: Rate of incidence of PaCO2 >/= 6.6kPa in the naloxone group compared to placebo

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    End point title
    		 Rate of incidence of PaCO2 >/= 6.6kPa in the naloxone group compared to placebo
    End point description
    End point type
    Secondary
    End point timeframe
    18-24 hours post administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: Subjects
    1
    11
    Statistical analysis title
    		 PaCO2 > 6.6kPa
    Statistical analysis description
    z-test for independent proportions
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 z test for independent proportions
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.0888
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.012
         upper limit
    		 0.6588

    Secondary: Maximum pain score

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    End point title
    		 Maximum pain score
    End point description
    End point type
    Secondary
    End point timeframe
    18 - 24 hours post administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: Pain score
        median (inter-quartile range (Q1-Q3))
    5 (4 to 8)
    4 (2 to 6)
    Statistical analysis title
    		 Maximum pain score
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009
    Method
    		 Mann-Whitney U test
    Confidence interval

    Secondary: Rescue fentanyl requirement

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    End point title
    		 Rescue fentanyl requirement
    End point description
    End point type
    Secondary
    End point timeframe
    18 - 24 hours after administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: mcg
        arithmetic mean (standard deviation)
    151 ± 117
    54 ± 80
    Statistical analysis title
    		 Rescue fentanyl
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.000025
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Patient Satisfaction score

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    End point title
    		 Patient Satisfaction score
    End point description
    End point type
    Secondary
    End point timeframe
    18 - 24 hours after administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: Satisfaction score Verbal rating 0-10
        median (inter-quartile range (Q1-Q3))
    8 (6 to 9)
    9 (7 to 10)
    Statistical analysis title
    		 Satisfaction scores
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Mann-Whitney U Test
    Confidence interval

    Secondary: Incidence of nausea in the naloxone vs placebo group

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    End point title
    		 Incidence of nausea in the naloxone vs placebo group
    End point description
    End point type
    Secondary
    End point timeframe
    18 - 24 hours after administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: Subjects
    25
    29
    Statistical analysis title
    		 Nausea
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.212
    Method
    		 z test for independent proportions
    Confidence interval

    Secondary: Vomiting

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    End point title
    		 Vomiting
    End point description
    End point type
    Secondary
    End point timeframe
    18 - 24 hours after administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: Subjects
    3
    5
    Statistical analysis title
    		 Vomiting
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.343
    Method
    		 z test for independent proportions
    Confidence interval

    Secondary: Rate of pruritus in the naloxone group vs placebo

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    End point title
    		 Rate of pruritus in the naloxone group vs placebo
    End point description
    End point type
    Secondary
    End point timeframe
    18 - 24 hours after administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: subjects
    15
    26
    Statistical analysis title
    		 Pruritus
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0123
    Method
    		 z test for independent proportions
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.92

    Secondary: Incidence of Ramsey score > / = 3 in the naloxone group vs placebo group

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    End point title
    		 Incidence of Ramsey score > / = 3 in the naloxone group vs placebo group
    End point description
    End point type
    Secondary
    End point timeframe
    18 - 24 hours after administration of intrathecal morphine
    End point values
    		 Naloxone Placebo
    Number of subjects analysed
    44
    43
    Units: subjects
    2
    4
    Statistical analysis title
    		 Ramsey score >/= 3
    Comparison groups
    Naloxone v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.326
    Method
    		 z test for independent proportions
    Confidence interval

    Other pre-specified: Respiratory depression diagnosed by RespiratoryMotion ExSpiron Xi or clinical observation.

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    End point title
    		 Respiratory depression diagnosed by RespiratoryMotion ExSpiron Xi or clinical observation.
    End point description
    End point type
    Other pre-specified
    End point timeframe
    18 - 24 hours after administration of intrathecal morphine
    End point values
    		 RespiratoryMotion ExSpiron Xi diagnosis Clinical observations diagnosis PaCO2 >6.6kPa RD Diagnosis
    Number of subjects analysed
    45
    45
    45
    Units: subjects
        Respiratory depression
    36
    16
    7
        No respiratory depression
    9
    29
    38
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 - 24 hours after administration of intrathecal morphine
    Adverse event reporting additional description
    Data was continuously collected during the trial period by the high dependency and PACU staff, including adverse events reports.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Naloxone
    Reporting group description
    		 Patients in this arm of the study will receive an infusion of naloxone at a rate of 5mcg/kg/hr from within one hour of extubation post operatively, until 08.00 the first postoperative morning.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received 0.9% Sodium Chloride via intravenous infusion at a rate of 0.25ml/kg/hr from within one hour of extubation postoperatively, until 08.00 the first postoperative morning.

    Serious adverse events
    		 Naloxone Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (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
    		 Naloxone Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 44 (2.27%)
    5 / 43 (11.63%)
    Injury, poisoning and procedural complications
    Tourniquet application
    Additional description: Tourniquet inadvertently left in place on arm following blood sampling for blood cultures during the study period, by a clinician not involved in the study. No morbidity occurred as a result.
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    Cardiac disorders
    Hypotension
    Additional description: Hypotension requiring vasopressor or aggressive fluid resuscitation during the study period.
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 43 (4.65%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Respiratory depression
    Additional description: Respiratory depression due to intrathecal morphine, requiring treatment with naloxone via intravenous infusion, outside of the trial protocol infusion.
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    Obstructive airways disorder
    Additional description: Excessive sedation postoperatively, leading to airway obstruction, treated with insertion of a nasopharyngeal airway, which successfully treated the complication.
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Apr 2017
    Statistics – update to Statistics section mainly to use more conservative, relative risk rather than odds ratio when determining the primary efficacy endpoint. Minor change to Statistical analysis to be more consistent with HPRA recommendations received in September 2015. Non-substantial change as this was already agreed in response back to HPRA. Method of assigning subjects to treatment groups - correction of an error in the description. Determination of sample size subjects – update to sample size. Total of 96 patients expected to participate, to allow for post randomisation loss to follow up / dropout.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29284510
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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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