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    Clinical Trial Results:
    Preanesthetic medication in pediatric patients: A comparison of midazolam, clonidine and dexmedetomidine

    Summary
    EudraCT number
    		 2015-003676-70
    Trial protocol
    		 SE  
    Global end of trial date
    30 Jun 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    01 Jan 2024
    First version publication date
    11 Oct 2022
    Other versions
    		 v1 , v2
    Version creation reason
    • Changes to summary attachments
    Adding links to manuscript 2 and 3

    Trial information

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    Trial identification
    Sponsor protocol code
    PedPreMed
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Region Norrbotten
    Sponsor organisation address
    Robertsviksgatan 7, Luleå, Sweden, 90187
    Public contact
    Magnus Hultin, Norrbottens läns landsting, 46 920282341, magnus.hultin@umu.se
    Scientific contact
    Magnus Hultin, Norrbottens läns landsting, 46 920282341, magnus.hultin@umu.se
    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
    30 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of this research is to compare three different preanesthetic medications (midazolam, clonidine and dexmedetomidine) in elective minor surgery under total intravenous anesthesia in pediatric patients for anxiolysis and sedation, hemodynamic stability and recovery profiles.
    Protection of trial subjects
    The trial was conducted in the normal perioperative pediatric flow at the hospital to ensure a close monitoring of the child while acute effects of the IMPs were studied. One parent was present with the child until the child was anesthetized in the operation theatre. During the preanesthetic phase there was a registered nurse present in the same room until the registered anesthetic nurse (RNA) brought the child and the parent to the operation theatre. During induction of anesthesia and until being delivered to the postoperative ward, and anesthesiologist (registered specialist physician) and the RNA was present all the time. At the postoperative ward a registered nurse attended the needs of the child in addition to having the parent present. For unexpected long-term effects after the child had left the hospital and the acute effect of the premedication (IMP) was undetectable, the parent had access to a study-telephone number in addition to being able to contact the surgeon or the emergency ward. Information about the trial was added to the patients electronic health registry (chart) and a procedure for breaking the code for the individual patient by opening a sealed envelope was in place 24/7/365 if it would have been necessary. The decision to break the code was left at the discretion of the attending at the intensive care unit of the hospital.
    Background therapy
    		 Preoperative lidocain/prilocain local cream 20 mg/g, 2g, paracetamol 30 mg/kg, ibuprofen oral solution 10 mg/kg, betamethasone, 0.3 mg/kg. Anesthesia with atropine 0.01 mg/kg iv, propofol and remifentanil infusion. Postoperative iv morphine 0.1-0.2 mg/kg and ondansetron 0.1 mg/kg.
    Evidence for comparator
    		 The comparators were three groups receiving oral midazolam, oral clonidine or intranasal dexmedetomidine as preanesthetic medication. Oral dexmedetomidine was not preferred because of poor bioavailability. Results from clinical trials in children, suggests that intranasal administration of dexmedetomidine is more effective as premedication, with adequate sedation achieved within 30 to 45 minutes (Cimen, Hanci, Sivrikaya, Kilinc, & Erol, n.d.; Zhang, Bai, Zhang, Wang, & Lu, 2013). Using oral preanesthetic, onset of sedation is significantly faster after premedication with oral midazolam (30 min) than with oral clonidine (60 min) (Almenrader, Passariello, Coccetti, Haiberger, & Pietropaoli, 2007). The compared premedications are oral midazolam 0.5 mg/kg, oral clonidine 4 μg/kg, and intranasal dexmedetomidine 2 μg/kg. These products are used “off label” as clinical routine in hospitals in Sweden and worldwide for sedation to children undergoing procedures. Course of therapy are current regimens, tested and recommended in clinical studies and by the Medical Products Agency (Almenrader et al., 2007; Cimen, Hanci, Sivrikaya, Kilinc, & Erol, n.d.; Zhang, Bai, Zhang, Wang, & Lu, 2013).
    Actual start date of recruitment
    01 Feb 2017
    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
    Sweden: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    90
    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
    		 The study took place in Region Norrbotten, Sweden. Patients were recruited between February 1, 2017 and May 6, 2017.

    Pre-assignment
    Screening details
    		 In total, 239 patients aged 2-6 years and planned for ENT surgery were assessed for eligibility. Due to shortness of research staff on the day of surgery (n=199), declined to participate (n=4), not meeting inclusion cirri (n=49) or being removed from the operation program (n=5), only 90 patients were randomized.

    Period 1
    Period 1 title
    Perioperative period (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
    A separate nurse, not involved in any of the other roles, performed the randomization by opening a sealed envelope, preparing and giving the three doses: two placebos and one with an active substance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CLO group
    Arm description
    		 Children who received clonidine 4 µg/kg oral solution 60 min before going to surgery
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clonidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Enteral use
    Dosage and administration details
    Clonidine APL, oral solution 20 µg/ml, 4 µg/kg (0.2 ml/kg), given per os 60 min before going to surgery

    Arm title
    		 MID group
    Arm description
    		 Children who received midazolam 0.5mg/kg oral solution 40 min before going to surgery
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Enteral use
    Dosage and administration details
    Clonidine APL, oral solution 1 mg/ml, 0.5 mg/kg (0.5 ml/kg), given per os 40 min before going to surgery

    Arm title
    		 DEX group
    Arm description
    		 Children who received dexmedetomidine 2 µg/kg intranasal 40 min before going to surgery
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexmedetomidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intranasal use
    Dosage and administration details
    Dexmedetomidine, 100 µg/ml, 2 µg/kg, 0.2 ml/kg (0.02 ml/kg) was given intranasally with a mucosal atomizing device ( https://www.teleflex.com/emea/en/product-areas/anaesthesia/atomization/mad-nasal-atomization-device/index.html) 40 min before going to surgery

    Number of subjects in period 1
    		CLO group MID group DEX group
    Started
    30
    30
    30
    Completed
    26
    27
    30
    Not completed
    4
    3
    0
         Refused to take IMP
    3
    3
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Perioperative period
    Reporting group description
    		 -

    Reporting group values
    		 Perioperative period Total
    Number of subjects
    		 90 90
    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)
    		 90 90
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 36 36
        Male
    		 54 54

    End points

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    End points reporting groups
    Reporting group title
    CLO group
    Reporting group description
    		 Children who received clonidine 4 µg/kg oral solution 60 min before going to surgery

    Reporting group title
    MID group
    Reporting group description
    		 Children who received midazolam 0.5mg/kg oral solution 40 min before going to surgery

    Reporting group title
    DEX group
    Reporting group description
    		 Children who received dexmedetomidine 2 µg/kg intranasal 40 min before going to surgery

    Primary: Preoperative anxiety

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    End point title
    		 Preoperative anxiety
    End point description
    End point type
    Primary
    End point timeframe
    Baselline Anesthesia preparation
    End point values
    		 CLO group MID group DEX group
    Number of subjects analysed
    27
    27
    30
    Units: mYPAS
        median (full range (min-max))
    0 (-8 to 67)
    0 (-13 to 77)
    0 (-13 to 63)
    Attachments
    		 mYPAS
    Statistical analysis title
    		 Effect on mYPAS
    Statistical analysis description
    Comparing the change in mYPAS from baseline until the child is asleep after three different premedications. The table and comparisons are shown in Table 2 in the published paper (https://doi.dx.org/10.1111/pan.14279)
    Comparison groups
    CLO group v MID group v DEX group
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.036 [1]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [1] - Comparing the differences in mYPAS at baseline and during anesthesia preparation.

    Secondary: Behavioral distress scale

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    End point title
    		 Behavioral distress scale
    End point description
    End point type
    Secondary
    End point timeframe
    60 min
    End point values
    		 CLO group MID group DEX group
    Number of subjects analysed
    27
    27
    30
    Units: Points
        median (full range (min-max))
    1 (0 to 3)
    1 (1 to 3)
    1 (0 to 6)
    Statistical analysis title
    		 Effect on distress at Peripheral cannula insertion
    Statistical analysis description
    Behavioral distress scale was assessed at insertion of peripheral cannula
    Comparison groups
    CLO group v MID group v DEX group
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.173 [2]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [2] - Non significant, i.e. no differences between groups

    Secondary: Induction compliance checklist

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    End point title
    		 Induction compliance checklist
    End point description
    The Childs compliance during induction
    End point type
    Secondary
    End point timeframe
    During induction of anesthesia
    End point values
    		 CLO group MID group DEX group
    Number of subjects analysed
    27
    27
    30
    Units: points
        median (full range (min-max))
    0 (0 to 7)
    0 (0 to 5)
    0 (0 to 7)
    Statistical analysis title
    		 ICC
    Comparison groups
    CLO group v MID group v DEX group
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.871
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Sedation level Anesthesia preparation

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    End point title
    		 Sedation level Anesthesia preparation
    End point description
    End point type
    Secondary
    End point timeframe
    at Anesthesia preparation
    End point values
    		 CLO group MID group DEX group
    Number of subjects analysed
    27
    27
    30
    Units: RSS
        median (full range (min-max))
    3 (2 to 5)
    2 (2 to 3)
    4 (2 to 5)
    Statistical analysis title
    		 RSS at anesthesia preparation
    Comparison groups
    CLO group v DEX group v MID group
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Time to recover from anesthesia and surgery

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    End point title
    		 Time to recover from anesthesia and surgery
    End point description
    Time to recover from anaesthesia and surgery defined as the time from arrival at the PACU until the criteria of discharge from PACU was reached using the Post Anesthesia Scoring System (PADSS)
    End point type
    Secondary
    End point timeframe
    First few hours after anesthesia
    End point values
    		 CLO group MID group DEX group
    Number of subjects analysed
    26
    26
    30
    Units: minutes
        median (full range (min-max))
    90 (38 to 162)
    76 (45 to 150)
    105 (60 to 325)
    Statistical analysis title
    		 Time until discharge criteria fulfilled
    Statistical analysis description
    Kruskal-Wallis for the time until the discharge criteria were fulfilled, comparing the three arms.
    Comparison groups
    CLO group v MID group v DEX group
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.211 [3]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [3] - No difference detected in time to full recovery from anesthesia between the groups

    Secondary: Emergence delirium

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    End point title
    		 Emergence delirium
    End point description
    PAED score ≥10p
    End point type
    Secondary
    End point timeframe
    The time period at the postoperative ward until being discharged
    End point values
    		 CLO group MID group DEX group
    Number of subjects analysed
    26
    26
    30
    Units: PAED > 10p
    3
    8
    1
    Statistical analysis title
    		 Emergence delirium
    Statistical analysis description
    Emergence delirium at any timepoint, defined as PAES score >10p
    Comparison groups
    CLO group v MID group v DEX group
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.013 [4]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [4] - The three premedications are likely to cause different proportions of children with emergence delirium after premedication + anesthesia with total intravenous anesthesia (propofol + remifentanil)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The full trial period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    CLO group
    Reporting group description
    		 Children who received clonidine 4 µg/kg oral solution 60 min before surgery

    Reporting group title
    MID group
    Reporting group description
    		 Children who received midazolam 0.5mg/kg oral solution 40 min before surgery

    Reporting group title
    DEX group
    Reporting group description
    		 Children who received dexmedetomidine 2 µg/kg intranasal 40 min before surgery

    Serious adverse events
    		 CLO group MID group DEX group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Surgical failure
    Additional description: During adenectomy unexpected liquor leak. The patient was referred to a university hospital for investigation and further treatment. It was considered a congenital malformation and completely unrelated to IMP or the surgeon.
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CLO group MID group DEX group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 27 (11.11%)
    9 / 27 (33.33%)
    6 / 30 (20.00%)
    Cardiac disorders
    Bradycardia
    Additional description: Heart frequency
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Delirium
    Additional description: Postoperative emergence delirium
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 27 (11.11%)
    0 / 30 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrointestinal disorders
    Nausea
    Additional description: Postoperative nausea and/or vomiting
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    3 / 30 (10.00%)
         occurrences all number
    0
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Laryngospasm
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 27 (14.81%)
    2 / 30 (6.67%)
         occurrences all number
    1
    4
    2
    Postoperative wound complication
    Additional description: small venous bleeding from the site of surgery
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Postoperative wound infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
    Additional description: General pruritus for two weeks after surgery
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
         occurrences all number
    0
    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.
    An interim analysis was performed after 90 included participants without breaking the code. The variance within the groups in the primary objective was smaller than expected, and the intended power had been reached. Thus the study was closed.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34403548
    http://www.ncbi.nlm.nih.gov/pubmed/36604221
    http://www.ncbi.nlm.nih.gov/pubmed/37528645
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