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    Clinical Trial Results:
    Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia in Patients following Groin-Hernia-Repair. A companion study to: Pharmacokinetics of High-dose Target-controlled Naloxone Infusion.

    Summary
    EudraCT number
    		 2015-000793-36
    Trial protocol
    		 DK  
    Global end of trial date
    14 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 May 2021
    First version publication date
    20 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HighNxGHR
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Multidisciplinary Pain Center 7612, Neuroscience Center
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Mads U. Werner, Multidisciplinary Pain Center 7612, Neuroscience Center, Rigshospitalet, 0045 28257703, mads.u.werner@gmail.com
    Scientific contact
    Mads U. Werner, Multidisciplinary Pain Center 7612, Neuroscience Center, Rigshospitalet, 0045 28257703, mads.u.werner@gmail.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
    11 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal aim of the study was to investigate the pharmacokinetic construct validity of a target-controlled-infusion (TCI) of naloxone.
    Protection of trial subjects
    During infusion of naloxone, participants will be monitored with ECG and measurements of pulse oximetry, blood pressure and respiratory rate. When naloxone is given, a physician and a nurse will be present if potential side effects should need any kind of treatment. If requested by the participant, the rapid-onset, analgesic, rescue-opioid, alfentanil, will be administered, which, in less than one min completely will antagonize the effects of naloxone. Alfentanil is a well- known drug used in anaesthesia for immediate relief of acute pain. Alfentanil is initially given 7-15 microg/kg (1-2 ml/70 kg) and is administered in a titrated fashion until the desired analgesic effect is achieved. Common dose-dependent side effects are nausea, vomiting and sedation (> 10%). During the naloxone-infusion, the participant’s resting pain is monitored. The naloxone-infusion is immediately stopped if the participant experiences pain levels > 5 (NRS 0-10).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Nov 2015
    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
    Denmark: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The PK-participants will be recruited from our registry of volunteers who previously have participated in experimental pain studies at the Multidisciplinary Pain Center 7612, Rigshospitalet.

    Pre-assignment
    Screening details
    		 Evaluation by a physician.

    Pre-assignment period milestones
    Number of subjects started
    		 8
    Number of subjects completed
    		 8

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Naloxone
    Arm description
    		 All subjects receiving naloxone infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Naloxone 4 mg/ml is delivered in glass ampoules of 100 ml (total content 400 mg). Naloxone is dissolved in a 0.9% NaCl solution: 1 liter of solution contains 9 grams of sodium chloride in sterile water (sodium-chloride 154 mmol/l; osmolarity 308 mmol/l). A total dose of 3.25 mg/kg of naloxone will be administered in a step-wise approach for 75 minutes as follows: In the first minute (0-1 min) a bolus of 0.02 mg/kg will be given followed by an infusion of 0.23 mg/kg during 24 minutes (1-25 min). Afterwards (25-26 min) a bolus of 0.06 mg/kg will be administered followed by a 24-minute infusion of 0.69 mg/kg (min 26-50). Finally, a bolus of 0.18 mg/kg (50-51 min) will be given followed by a 24-minute infusion of 2.07 mg/kg (51-75 min).

    Number of subjects in period 1
    		Naloxone
    Started
    8
    Completed
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 8 8
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 8 8
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 25.9 (24.4 to 28.9) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 8 8
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    		 182 (177 to 194) -
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    		 79.6 (61 to 92) -
    Subject analysis sets

    Subject analysis set title
    Final analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in the study adhered to the same analysis set.

    Subject analysis sets values
    		 Final analysis
    Number of subjects
    8
    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)
    8
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    25.9 (24.4 to 28.9)
    Gender categorical
    Units: Subjects
        Female
    0
        Male
    8
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    182 (177 to 194)
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    79.6 (61 to 92)

    End points

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    End points reporting groups
    Reporting group title
    Naloxone
    Reporting group description
    		 All subjects receiving naloxone infusion

    Subject analysis set title
    Final analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in the study adhered to the same analysis set.

    Primary: Plasma concentration of naloxone

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    End point title
    		 Plasma concentration of naloxone [1]
    End point description
    End point type
    Primary
    End point timeframe
    Time-points during the TCI-infusion 17,20,23,41,44,47,67,70 and 75 min, and after 76,77,78, 79,80,82,86,94,110,142,206 and 334 min.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analyses made in the current study was by population pharmacokinetics. This cannot be described by the terms provided here. No pairwise comparisons were made.
    End point values
    		 Naloxone Final analysis
    Number of subjects analysed
    8
    8
    Units: ng/ml
        geometric mean (confidence interval 95%)
    455.37 (399.77 to 510.97)
    455.37 (399.77 to 510.97)
    Attachments
    		 Concentration-time profiles for naloxone
    No statistical analyses for this end point

    Primary: Plasma concentration of naloxone-3-glucuronide

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    End point title
    		 Plasma concentration of naloxone-3-glucuronide [2]
    End point description
    End point type
    Primary
    End point timeframe
    Time-points during the TCI-infusion 17,20,23,41,44,47,67,70 and 75 min, and after 76,77,78, 79,80,82,86,94,110,142,206 and 334 min.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analyses made in the current study was by population pharmacokinetics. This cannot be described by the terms provided here. No pairwise comparisons were made.
    End point values
    		 Naloxone Final analysis
    Number of subjects analysed
    8
    8
    Units: ng/ml
        geometric mean (confidence interval 95%)
    1220.94 (1098.18 to 1343.69)
    1220.94 (1098.18 to 1343.69)
    Attachments
    		 Concentration-time profiles for naloxone
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time 0 min when the infusion starts to time 340 min when the participant is discharged.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Naloxone
    Reporting group description
    		 All subjects receiving naloxone infusion

    Serious adverse events
    		 Naloxone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Naloxone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    General disorders and administration site conditions
    Anxiety
    Additional description: The subject experienced general discomfort and anxiety at the beginning of the naloxone infusion.
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    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.
    The values for the endpoints given as mean (95%CI) do not provide valuable information, since the main objective of the current study is to measure concentrations of naloxone. We refer to the attached chart under the endpoints section.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30915992
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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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