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    Clinical Trial Results:
    Highdose steroids in High Pain Responders undergoing total knee-arthroplasty - A randomized doubleblindet controlled trial.

    Summary
    EudraCT number
    		 2018-002635-23
    Trial protocol
    		 DK  
    Global end of trial date
    01 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2022
    First version publication date
    23 Sep 2022
    Other versions
    Summary report(s)
    		 Journal article, BJA 2021

    Trial information

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    Trial identification
    Sponsor protocol code
    NBF_HK_02_2018.
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03763734
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Anesthesia-research group of Prof. Nicolai Bang Foss
    Sponsor organisation address
    Kettegård alle 30, Hvidovre , Denmark, 2650
    Public contact
    Niklas Ingemann Nielsen, Anesthesia-Research group., Anaesthesia Department, Hvidovre Hospital, Capital Region of Denmark, +45 38623862, Niklas.Ingemann.Nielsen@regionh.dk
    Scientific contact
    Niklas Ingemann Nielsen, Anesthesia-Research group., Anaesthesia Department, Hvidovre Hospital, Capital Region of Denmark, +45 38623862, Niklas.Ingemann.Nielsen@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
    11 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of high dose steroids on the amount of patients with VAS >30 in a 5-meter walktest, 24 hours postoperatively efter total kneearthroplasty in a High Pain responder cohort.
    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, Local Infiltration Analgesia applied by the surgeon perioperatively, postoperative compression bandage. Perioperative antibiotic regimen of i.v. dicloxacillin 2 g at start of surgery and repeated if body weight >80 kg or if length of surgery >2 h. Dicloxacillin was repeated as 1 g tablet 8 h after end of surgery. Cefuroxim in case of allergy. 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. T.H. Lunn, B.B. Kristensen, L. Andersen, et al. Effect of high-dose preoperative methylprednisolone on pain and recovery after total knee arthroplasty: a randomized, placebo-controlled trial Br J Anaesth, 106 (2011), pp. 230-238 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 meta-analysis 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?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 88
    Worldwide total number of subjects
    88
    EEA total number of subjects
    88
    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)
    25
    From 65 to 84 years
    62
    85 years and over
    1

    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 August 2020.

    Pre-assignment
    Screening details
    		 From February 13, 2019 to August 26, 2020, a total of 1037 patients planned for knee arthroplasty were assessed for inclusion in accordance to inclusion and exclusioncriteria. 25% of screened patients were eligible and 88 patients were included and randomised.

    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
    Randomisation 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 (High dose, HD)
    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
    Infusion
    Routes of administration
    Intravenous drip use
    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 1mg/kg. Infusion initiated after application of neuraxial anesthesia and administered within 10-15 minutes.

    Arm title
    		 Control (standard/intermediate dose (ID)
    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
    Infusion
    Routes of administration
    Intravenous drip use
    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 (High dose, HD) Control (standard/intermediate dose (ID)
    Started
    44
    44
    Completed
    42
    42
    Not completed
    2
    2
         excluded due to change of surgery/anesthesia
    2
    2

    Baseline characteristics

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

    Reporting group title
    Control (standard/intermediate dose (ID)
    Reporting group description
    		 Intermediate dose dexamethasone 0.3mg/kg of actual bodyweight

    Reporting group values
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID) Total
    Number of subjects
    		 44 44 88
    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))
    		 70 (50 to 86) 70 (50 to 82) -
    Gender categorical
    Sex (n/n)
    Units: Subjects
        Female
    		 16 16 32
        Male
    		 28 28 56
    ASA-score
    ASA-score American Society of Anesthesiologist score of morbidity and physical status. Range I-VI (1-6) ranging from I: Healthy patient to VI: Brain-dead patient awaiting organ-donation.
    Units: Subjects
        Score I
    		 7 7 14
        Score II
    		 20 31 51
        Score III
    		 17 6 23

    End points

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

    Reporting group title
    Control (standard/intermediate dose (ID)
    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 (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [1]
    42 [2]
    Units: Percentage
        VAS>30
    21
    33
        VAS<31
    21
    9
    Notes
    [1] - 2 patients excluded before intervention
    [2] - 2 patients excluded before intervention
    Statistical analysis title
    		 Chi-squared test.
    Statistical analysis description
    Chi-squared test of significance
    Comparison groups
    Control (standard/intermediate dose (ID) v Intervention (High dose, HD)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Chi-squared
    Confidence interval

    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 (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [3]
    42 [4]
    Units: mm
    median (inter-quartile range (Q1-Q3))
        VAS score
    30 (18 to 58)
    45 (32 to 58)
    Attachments
    		 Distribution of VAS at 24h (median(IQR))
    Notes
    [3] - 2 patients excluded before intervention
    [4] - 2 patients excluded before intervention
    Statistical analysis title
    		 Mann-whitney U test
    Statistical analysis description
    Mann-whitney
    Comparison groups
    Intervention (High dose, HD) v Control (standard/intermediate dose (ID)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    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 (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [5]
    42 [6]
    Units: (n/n, %)
        VAS>30
    11
    18
        VAS<31
    31
    24
    Notes
    [5] - 2 patients excluded before intervention
    [6] - 2 patients excluded before intervention
    Statistical analysis title
    		 Chi-squared
    Comparison groups
    Control (standard/intermediate dose (ID) v Intervention (High dose, HD)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Chi-squared
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Cumulated pain day 0-2 upon rest

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    End point title
    		 Cumulated pain day 0-2 upon rest
    End point description
    Cumulted pain scores (VAS 0-100mm) on day 0-2, median(IQR)
    End point type
    Secondary
    End point timeframe
    0-48 hours after surgery (prespecified timeframe of 1 hour before and after actual end of surgery timepoint).
    End point values
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [7]
    42 [8]
    Units: mm
    median (inter-quartile range (Q1-Q3))
        Cumulated pain 0-2
    80 (37 to 112)
    86 (69 to 143)
    Notes
    [7] - 2 patients excluded before intervention
    [8] - 2 patients excluded before intervention
    No statistical analyses for this end point

    Secondary: Cumulated pain day 0-2 upon ambulation

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    End point title
    		 Cumulated pain day 0-2 upon ambulation
    End point description
    Cumulted pain scores (VAS 0-100mm) on day 0-2, median(IQR) upon ambulation in a 5m walk test
    End point type
    Secondary
    End point timeframe
    0-48 hours after surgery (prespecified timeframe of 1 hour before and after actual end of surgery timepoint).
    End point values
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [9]
    42 [10]
    Units: VAS (MM)
    median (inter-quartile range (Q1-Q3))
        Cumulated pain day 0-2 upon ambulation
    82 (45 to 118)
    101 (69 to 131)
    Notes
    [9] - 2 patients excluded before intervention
    [10] - 2 patients excluded before intervention
    No statistical analyses for this end point

    Secondary: Cumulated pain day 0-2 upon passive legg raise

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    End point title
    		 Cumulated pain day 0-2 upon passive legg raise
    End point description
    Cumulted pain scores (VAS 0-100mm) on day 0-2, median(IQR)
    End point type
    Secondary
    End point timeframe
    0-48 hours after surgery (prespecified timeframe of 1 hour before and after actual end of surgery timepoint).
    End point values
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [11]
    42 [12]
    Units: VAS (MM)
    median (inter-quartile range (Q1-Q3))
        Cumulated pain day 0-2 upon passive legg raise
    23 (0 to 81)
    67 (28 to 110)
    Notes
    [11] - 2 patients excluded before intervention
    [12] - 2 patients excluded before intervention
    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 (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [13]
    42 [14]
    Units: mg/L
    median (inter-quartile range (Q1-Q3))
        CRP 24 hours
    13 (8 to 23)
    21 (9 to 34)
        CRP 48 hours
    23 (12 to 35)
    51 (39 to 83)
    Notes
    [13] - 2 patients excluded before intervention
    [14] - 2 patients excluded before intervention
    Statistical analysis title
    		 Mann-whitney
    Comparison groups
    Intervention (High dose, HD) v Control (standard/intermediate dose (ID)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [15]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - p=0.01 at 24h and p<0.01 at 48h.

    Secondary: Cumulated opioid-use day 0-2

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    End point title
    		 Cumulated opioid-use day 0-2
    End point description
    Cumulated opioid-use presented as oral morphine in mg., cumulated day 0-2.
    End point type
    Secondary
    End point timeframe
    Postoperative day 0-2 reported at timepoints 24h and 48h after surgery
    End point values
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [16]
    42 [17]
    Units: mg
    median (inter-quartile range (Q1-Q3))
        Day 0-2
    51 (30 to 90)
    83 (46 to 111)
    Notes
    [16] - 2 patients excluded prior to randomization
    [17] - 2 patients excluded prior to randomization
    Statistical analysis title
    		 Significance test
    Statistical analysis description
    Mann-whitney significance test
    Comparison groups
    Intervention (High dose, HD) v Control (standard/intermediate dose (ID)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.06
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cumulated opioid-use

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    End point title
    		 Cumulated opioid-use
    End point description
    Cumulated opioid-use presented as oral morphine in mg., cumulated day 2-7.
    End point type
    Secondary
    End point timeframe
    Postoperative day 2-7 reported at timepoints from evening day 2 and onto evening day 7 after surgery
    End point values
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Number of subjects analysed
    42 [18]
    42 [19]
    Units: mg
    median (inter-quartile range (Q1-Q3))
        Day 2-7
    95 (18 to 185)
    150 (45 to 255)
    Notes
    [18] - 2 participants excluded prior to intervention
    [19] - 2 participants excluded prior to intervention
    Statistical analysis title
    		 Significance test
    Statistical analysis description
    Mann-whitney U test
    Comparison groups
    Intervention (High dose, HD) v Control (standard/intermediate dose (ID)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.12
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    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 (High dose, HD)
    Reporting group description
    		 Intervention arm, High dose Dexamethasone 1mg/kg of patient's actual bodyweight.

    Reporting group title
    Control (standard/intermediate dose (ID)
    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 reported, as specified in the protocol and agreed upon by the Local ethics committee and relevant authorities(DKMA)
    Serious adverse events
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 42 (4.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Patellar dislocation
    Additional description: Patellar dislocation needing revision surgery
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    Additional description: Skin-infection, deep wound infection needing further antibiotics or Prosthetic joint infection needing revision
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34749994
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