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    Clinical Trial Results:
    Highdose steroid for total knee arthroplasty - A randomized doubleblindet controlled trial.

    Summary
    EudraCT number
    2018-002634-20
    Trial protocol
    DK  
    Global end of trial date
    01 Feb 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Sep 2022
    First version publication date
    26 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NBF_HK_01_2018
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03758170
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hvidovre Hospital
    Sponsor organisation address
    Kettegaards alle 30, Hvidovre, Denmark, 2650
    Public contact
    Research group, anaesthesia Dept., Anaesthesia Department, Hvidovre Hospital, Capital Region of Denmark, +45 38623862, Nicolai.Bang.Foss@regionH.dk
    Scientific contact
    Research group, anaesthesia Dept., Anaesthesia Department, Hvidovre Hospital, Capital Region of Denmark, +45 38623862, Nicolai.Bang.Foss@regionH.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
    01 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the amount of patients with VAS >30 in a 5-meter walk test, 24 hours postoperatively efter total kneearthroplasty.
    Protection of trial subjects
    All patients had standardized care, surgery, and treatments as part of a Fast-track surgery regimen in Total Knee Arthroplasty surgery, and both study-treatment-groups had active treatment (standard-dose vs. higher dose).
    Background therapy
    Multimodal opioid-sparring analgesia including Cox-2 inhibitors, acetaminophen(paracetamol) and rescue opioids (morphine or oxycodone). All patients had pre- and postoperative tranexamic acid. Thromboprophylaxis was used in-hospital only (xarelto or eliquis). All patients had neuraxial anesthesia with bupivacaine.
    Evidence for comparator
    The use of steroids as a perioperative mean of reducing postoperative stress and hence reducing postoperative pain is well-known, and several articles exist on the topic. Lunn TH, Andersen LO, Kristensen BB, Husted H, Gaarn-Larsen L, Bandholm T, Ladelund S, Kehlet H: Effect of high-dose preoperative methylprednisolone on recovery after total hip arthroplasty: A randomized, double-blind, placebo-controlled trial. Br J Anaesth 2013; 110:66–73 De Oliveira GS, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: A meta-analysis of randomized controlled trials. Anesthesiology 2011; 115: 575–88 C.C. Jørgensen, F.T. Pitter, H. Kehlet Safety aspects of preoperative high-dose glucocorticoid in primary total knee replacement Br J Anaesth, 119 (2017), pp. 267-275 A. Toner, V. Ganeshanathan, M. Chan, K. Ho, T. Corcoran Safety of perioperative glucocorticoids in elective noncardiac surgery, a systematic review and metaanalysis Anesthesiology, 126 (2017), pp. 234-248
    Actual start date of recruitment
    03 Dec 2018
    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: 157
    Worldwide total number of subjects
    157
    EEA total number of subjects
    157
    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)
    40
    From 65 to 84 years
    113
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited before surgery at their information meeting. All participants had had oral and written project information in accordance with guidelines and had at least 24 hours of consideration. All participants gave informed consent. Patients were screened at Hvidovre Hospital and Vejle sygehus from January 2019 to September 2021

    Pre-assignment
    Screening details
    From January 29, 2019, to september 31, 2021, a total of 1277 patients planned for hip arthroplasty were assessed for inclusion in accordance with inclusion and exclusion criteria. 75% of screened patients were eligible and 160 patients were included and 157 randomized.

    Period 1
    Period 1 title
    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
    Randomization sequence were made by unblinded physicians not otherwise connected to the study or the participants with double-control. Study-specific trained unblinded nurses at each site, not having any contact with the participants were responsible for preparing the study drug and blinding this for all other personnel. Study-drug was mixed into a blinded 100 ml. container, and intervention and control were alike in both volume and appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Intervention
    Arm description
    Intervention arm, High dose Dexamethasone 1mg/kg of patient's actual bodyweight.
    Arm type
    Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Dexamethasone 10mg/ml, added to a 100 ml. NaCl container in accordance with the patient's actual weight, thus the intervention dose was 1mg/kg. Infusion initiated after application of neuraxial anesthesia and administered within 10-15 minutes.

    Arm title
    Intermediate comparator
    Arm description
    Intermediate dose dexamethasone 0.3mg/kg of actual bodyweight
    Arm type
    Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    Dexamethasone 10mg/ml, added to a 100 ml. NaCl container in accordance to the patient's actual weight, thus the intervention dose was 0.3mg/kg. Infusion initiated after application of neuraxial anesthesia and administered within 10-15 minutes.

    Number of subjects in period 1
    Intervention Intermediate comparator
    Started
    80
    77
    Completed
    80
    77

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    Intervention arm, High dose Dexamethasone 1mg/kg of patient's actual bodyweight.

    Reporting group title
    Intermediate comparator
    Reporting group description
    Intermediate dose dexamethasone 0.3mg/kg of actual bodyweight

    Reporting group values
    Intervention Intermediate comparator Total
    Number of subjects
    80 77 157
    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
    Age
    Units: years
        median (full range (min-max))
    72 (46 to 87) 68 (43 to 89) -
    Gender categorical
    Gender, female
    Units: Subjects
        Female
    51 36 87
        Male
    29 41 70
    ASA
    ASA-score
    Units: Subjects
        ASA 1
    5 11 16
        ASA 2
    63 46 109
        ASA 3
    12 20 32
    Body mass index
    BMI
    Units: Kg/M3
        median (inter-quartile range (Q1-Q3))
    30 (27 to 34) 28 (25 to 32) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    Intervention arm, High dose Dexamethasone 1mg/kg of patient's actual bodyweight.

    Reporting group title
    Intermediate comparator
    Reporting group description
    Intermediate dose dexamethasone 0.3mg/kg of actual bodyweight

    Primary: Primary Outcome: Percentage of patients experiencing VAS>30mm on a 0-100 mm. VAS scale 24 hours after surgery upon ambulation

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    End point title
    Primary Outcome: Percentage of patients experiencing VAS>30mm on a 0-100 mm. VAS scale 24 hours after surgery upon ambulation
    End point description
    Percentage of patients experiencing VAS>30mm on a 0-100 mm VAS scale 24 hours after surgery upon ambulation in a 5 meter walk test.
    End point type
    Primary
    End point timeframe
    24 hours after knee replacement surgery (a timeframe of 1 hour before and after precise timepoint of end of surgery).
    End point values
    Intervention Intermediate comparator
    Number of subjects analysed
    80
    77
    Units: Number/percentage
        Mild pain (<30 mm on VAS 0-100 mm)
    35
    36
        Moderate to severe pain (>30 mm on VAS 0-100 mm)
    45
    41
    Statistical analysis title
    Chi squared primary outcome
    Comparison groups
    Intervention v Intermediate comparator
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.65
    Method
    Chi-squared
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.4

    Secondary: PAIN (VAS-score) 24hours after surgery upon ambulation

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    End point title
    PAIN (VAS-score) 24hours after surgery upon ambulation
    End point description
    VAS-score upon ambulation in a 0-100mm. VAS scale upon a 5 meter walk test 24 hours after surgery.
    End point type
    Secondary
    End point timeframe
    24 hours after surgery (prespecified timeframe of 1 hour before and after actual end of surgery timepoint).
    End point values
    Intervention Intermediate comparator
    Number of subjects analysed
    80
    77
    Units: VAS score in mm
        median (inter-quartile range (Q1-Q3))
    34 (19 to 50)
    35 (17 to 57)
    Statistical analysis title
    Mann whitney
    Comparison groups
    Intervention v Intermediate comparator
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.88
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: VAS>30mm 24hours after surgery upon rest

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    End point title
    VAS>30mm 24hours after surgery upon rest
    End point description
    Percentage of patients experiencing VAS>30mm upon rest in a 0-100mm. VAS scale 24 hours after surgery.
    End point type
    Secondary
    End point timeframe
    24 hours after surgery (prespecified timeframe of 1 hour before and after actual end of surgery timepoint).
    End point values
    Intervention Intermediate comparator
    Number of subjects analysed
    80
    77
    Units: number
        >30 mm on 0-100 mm VAS
    26
    20
        <30 mm on 0-100mm VAS
    54
    57
    No statistical analyses for this end point

    Secondary: CRP after surgery

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    End point title
    CRP after surgery
    End point description
    C-reactive protein (CRP) as a measure of inflammatory response (mg/L)
    End point type
    Secondary
    End point timeframe
    24 and 48 hour after surgery
    End point values
    Intervention Intermediate comparator
    Number of subjects analysed
    80
    77
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    13 (6 to 25)
    16 (9 to 38)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Serious adverse events were reported on day 0, 1, 2, 7, 30 or 90, or when alerted via our electronic patient record-system, and all SAE were reported within 24h of alert to the Sponsor.
    Adverse event reporting additional description
    Only Serious adverse events were recorded and reported in accordance with the approval of the Danish medicines agency and local ethics committee, as Dexamethasone is a broadly used and well-approved drug. If adverse events (not serious adverse events) were reported or suspected of occurring in more than 5% of patients, the sponsor was informed.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Intervention 1mg/kg
    Reporting group description
    Intervention arm, High dose Dexamethasone 1mg/kg of patient's actual bodyweight.

    Reporting group title
    Intermediate 0.3 mg/kg
    Reporting group description
    Intermediate dose dexamethasone 0.3mg/kg of actual bodyweight

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events were recorded, as accepted in the protocol by the local ethics committee and DKMA
    Serious adverse events
    Intervention 1mg/kg Intermediate 0.3 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 80 (8.75%)
    3 / 77 (3.90%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis postoperative
    Additional description: Deep vein thrombosis postoperative, assessed to be due to lack of mobilization after discharge.
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    Additional description: Atrial fibrillation in a patient not formerly known to have atrial fibrillation
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
    Additional description: 2. degree AV- block demanding insertion of a pacemaker.
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Soft tissue infection
    Additional description: Postoperative soft tissue infection in the area of surgery, treated by antibiotics, no revision needed.
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
    Additional description: Postoperative wound infection including the arthroplasty and demanding revision surgery
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Intervention 1mg/kg Intermediate 0.3 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 77 (0.00%)

    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? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    Elective surgery was shut down due to the global Covid crisis.
    02 Jun 2020

    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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