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    Clinical Trial Results:
    The use of intraoperative methadone in children undergoing minor open urological surgery

    Summary
    EudraCT number
    		 2020-002945-41
    Trial protocol
    		 DK  
    Global end of trial date
    22 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2024
    First version publication date
    31 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    78464317
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04680286
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Blvd. 99, Aarhus, Denmark, 8200
    Public contact
    Camilla Gaarsdal Uhrbrand , Aarhus University Hospital , 0045 23956082, camgaa@rm.dk
    Scientific contact
    Lone Nikolajsen, Aarhus University Hospital , lone.nikolajsen@clin.au.dk
    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
    14 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jan 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the effect of a single dose of intraoperative methadone on postoperative opioid requirements and pain intensity among children with undescended testes undergoing outpatient orchiopexy. 1) Administration of opioids in the PACU(yes/no) 2) The number of children with a pain intensity of 5 or higher on the FLACC scale within the first 3 h after laryngeal mask airway removal (yes/no).
    Protection of trial subjects
    Children were treated with our standard of care and the intervention was an addition to this. In this way children were not put in an increased risk of pain. Intervention was during anesthesia and did not distress the children.
    Background therapy
    		 Anesthesia, surgery and postoperative pain management were aligned in both groups: Anesthesia was induced with either propofol (3–5 mg/kg) or sevoflurane (5%–8%). Before or immediately following induction, a peripheral venous catheter was inserted, and fentanyl (1–2 μg/kg) and dexamethasone (0.2 mg/kg) were administered. In relation to induction of anesthesia, children received intravenous acetaminophen (50 mg/kg/day) and naproxen suppository (5 mg/kg/day). All children had a laryngeal mask airway. Anesthesia was maintained with remifentanil (20–50 μg/kg/h) and propofol (5–10 mg/kg/h) and no additional fentanyl was administered during anesthesia. Standard monitoring included electrocardiography, capnography, and pulse oximetry. Upon closure of the skin, local infiltration analgesia with bupivacaine 2.5 mg/mL (0.5–1 mL/kg) was administered by the surgeon. In brief, surgery was carried out through inguinal access, where the undescended testicle was moved from the inguinal region to the scrotum and fixed there. In the PACU, fentanyl (0.5–1 μ g/kg) was always the first choice for pain treatment. If several doses of fentanyl were inadequate, intravenous morphine (0.05 mg/kg) could be used. Before discharge, parents received oral and written information along with a written plan for at-home pain management. This plan consisted of acetaminophen (50 mg/kg/day three to four daily doses), naproxen (5 mg/kg/day twice daily) around the clock for the first 2 days and rescue morphine (0.2 mg/kg) reserved for breakthrough pain.
    Evidence for comparator
    		 The comparator was placebo (saline).
    Actual start date of recruitment
    28 Dec 2020
    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: 68
    Worldwide total number of subjects
    68
    EEA total number of subjects
    68
    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)
    35
    Children (2-11 years)
    33
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Children recruited were all planned for surgery at Aarhus University Hospital from December 2020 until January 2024. Parents were informed at a preoperative anesthesia assesment, and both parents had to consent.

    Pre-assignment
    Screening details
    		 147 children were screened for inclusion. 9 declined to participate. 43 met exclusion criterias (i.e.: multiple procedures planned, born premature, parents not speaking danish). In 27 cases the hospital pharmacy could not deliver/the surgery was cancelled. After inclusion of 68 children: 4 had a fever on operation day, and 4 for other reasons.

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    The medicine was prepared by the hospital pharmacy. Children, parents, hospital personnel (anesthetist, surgeon, post anesthesia care unit (PACU) nurses), and investigators were blinded to the randomization. The manuscript, along with its conclusion, was written before the data were unblinded through retrieval of an A- and B- list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 0.1 mg/kg methadone intraoperatively.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methadone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.1 mg/kg administered after insertion of laryngeal mask airway.

    Arm title
    		 Placebo
    Arm description
    		 Saline
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    NatriumChlorid
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Volume corresponding to that of the experimental. Administered after insertion og laryngeal mask airway.

    Number of subjects in period 1
    		Intervention Placebo
    Started
    34
    34
    Completed
    29
    31
    Not completed
    5
    3
         subsequent discovery of inclusion violation
    -
    1
         surgery not needed
    1
    -
         study drug not able to be produced
    2
    -
         fever
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 0.1 mg/kg methadone intraoperatively.

    Reporting group title
    Placebo
    Reporting group description
    		 Saline

    Reporting group values
    		 Intervention Placebo Total
    Number of subjects
    		 34 34 68
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        least squares mean (standard deviation)
    		 27 ( 2.8 ) 25.4 ( 2.4 ) -
    Gender categorical
    gender
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 34 34 68
    weight
    Units: kilogram(s)
        least squares mean (standard deviation)
    		 13.7 ( 3.3 ) 13.1 ( 2.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 0.1 mg/kg methadone intraoperatively.

    Reporting group title
    Placebo
    Reporting group description
    		 Saline

    Primary: Opioid administration in the PACU

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    End point title
    		 Opioid administration in the PACU
    End point description
    Did patients receive opioids during their PACU stay (yes/no).
    End point type
    Primary
    End point timeframe
    PACU
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: number
    5
    13
    Statistical analysis title
    		 primary
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.037
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.49

    Primary: FLACC ≥ 5 in the PACU

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    End point title
    		 FLACC ≥ 5 in the PACU
    End point description
    End point type
    Primary
    End point timeframe
    PACU
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: Number
    5
    10
    Statistical analysis title
    		 primary
    Comparison groups
    Placebo v Intervention
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.179
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.06

    Secondary: Time from surgery end to removal of the laryngeal mask airway

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    End point title
    		 Time from surgery end to removal of the laryngeal mask airway
    End point description
    End point type
    Secondary
    End point timeframe
    Surgery date
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: minute
    least squares mean (standard deviation)
        perioperative data
    14.2 ( 4.9 )
    14.1 ( 5.4 )
    No statistical analyses for this end point

    Secondary: Time to readiness to discharge from PACU

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    End point title
    		 Time to readiness to discharge from PACU
    End point description
    End point type
    Secondary
    End point timeframe
    PACU
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: minute
        least squares mean (standard deviation)
    145.4 ( 65.5 )
    114.6 ( 34.7 )
    No statistical analyses for this end point

    Secondary: Episodes of desaturation

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    End point title
    		 Episodes of desaturation
    End point description
    Defined as a saturation below 90% not overcome by simple actions.
    End point type
    Secondary
    End point timeframe
    PACU
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: numbers
    1
    1
    No statistical analyses for this end point

    Secondary: Awakenings on the first night

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    End point title
    		 Awakenings on the first night
    End point description
    End point type
    Secondary
    End point timeframe
    The night between the day of operation and the first day following.
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: numbers
    13
    13
    No statistical analyses for this end point

    Secondary: Awake due to pain

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    End point title
    		 Awake due to pain
    End point description
    Assesed by parents, how many children woke up due to pain
    End point type
    Secondary
    End point timeframe
    At home
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: numbers
    1
    7
    No statistical analyses for this end point

    Secondary: At-home pain intensities

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    End point title
    		 At-home pain intensities
    End point description
    End point type
    Secondary
    End point timeframe
    At home (36 hours).
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: FLACC
    29
    31
    Attachments
    		 Untitled (Filename: Figure2..png)
    No statistical analyses for this end point

    Other pre-specified: Anesthesia duration

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    End point title
    		 Anesthesia duration
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Surgery date
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: minute
    median (inter-quartile range (Q1-Q3))
        perioperative data
    69 (62 to 79)
    74 (61 to 86)
    No statistical analyses for this end point

    Other pre-specified: Surgery duration

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    End point title
    		 Surgery duration
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Surgery date
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    29
    31
    Units: minute
    median (inter-quartile range (Q1-Q3))
        perioperative data
    33 (25 to 43)
    29 (26 to 46)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of anesthesia and 4 days following.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 LMST
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 0.1 mg/kg methadone intraoperatively.

    Reporting group title
    Placebo
    Reporting group description
    		 Saline

    Serious adverse events
    		 Intervention Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 31 (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: 1%
    Non-serious adverse events
    		 Intervention Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 31 (6.45%)
    Gastrointestinal disorders
    Constipation
    Additional description: Short period where parents assesed constipated. Concurred the following day.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
    Additional description: Short hypoxia (85%) in the PACU. Patient was sick the week prior to surgery and was believed to have some residual secrete/mucus following anesthesia.
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    Infections and infestations
    fever
    Additional description: Patient had fever the night following surgery. The family contacted the emergency department. However, no treatment was started. No relation to intervention.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 31 (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 inclusion of children was challenged by the COVID-19 pan- demic, which extended the trial period and introduced the risk of change in clinical practice over time. However, the study protocol was strictly followed throughout the trial period.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/39306760
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