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    Clinical Trial Results:
    Highdose Steroid for High Pain Responders undergoing Total Hip-arthroplasty - A randomized doubleblindet controlled trial.

    Summary
    EudraCT number
    		 2018-002636-25
    Trial protocol
    		 DK  
    Global end of trial date
    01 Mar 2021

    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_03_2018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03763760
    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
    Research group, Anaesthesia Department, Hvidovre Hospital, Capital Region of Denmark., +45 38623862, Niklas.Ingemann.Nielsen@regionh.dk
    Scientific contact
    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
    10 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Nov 2020
    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 hip-arthroplasty 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 Hip 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: 160
    Worldwide total number of subjects
    160
    EEA total number of subjects
    160
    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)
    47
    From 65 to 84 years
    109
    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 July 2020.

    Pre-assignment
    Screening details
    		 From January 29, 2019, to July 16, 2020, a total of 1247 patients planned for hip arthroplasty were assessed for inclusion in accordance with inclusion and exclusion criteria. 25% of screened patients were eligible and 160 patients were included and randomized.

    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
    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 (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 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
    		 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
    80
    80
    Completed
    75
    75
    Not completed
    5
    5
         Consent withdrawn by subject
    -
    1
         Revision surgery before 24h
    -
    1
         excluded due to change of surgery/anesthesia
    5
    3

    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
    		 80 80 160
    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 (inter-quartile range (Q1-Q3))
    		 71 (66 to 76) 69 (60 to 75) -
    Gender categorical
    sex (n/n)
    Units: Subjects
        Female
    		 33 24 57
        Male
    		 47 56 103
    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
    		 14 15 29
        Score II
    		 51 54 105
        Score III
    		 15 11 26
    DASI score
    Duke activity status index score, an index to characterize physical performance before surgery
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 24 (15 to 35) 24 (15 to 31) -
    Bodymass index
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 30 (26 to 32) 28 (25 to 33) -

    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
    75 [1]
    75 [2]
    Units: percentage
        VAS>30
    33
    32
        VAS<31
    42
    44
    Notes
    [1] - 5 patients excluded before analysis
    [2] - 5 patients excluded before analysis
    Statistical analysis title
    		 Significance test
    Statistical analysis description
    Chi-squared test
    Comparison groups
    Intervention (High dose, HD) v Control (standard/intermediate dose (ID)
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.814
    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
    75
    75
    Units: mm
    median (inter-quartile range (Q1-Q3))
        Vas-score
    29 (13 to 47.5)
    24 (9 to 45.5)
    Statistical analysis title
    		 significance test
    Comparison groups
    Intervention (High dose, HD) v Control (standard/intermediate dose (ID)
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.459
    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
    75
    75
    Units: (n/n, %)
        VAS >30
    23
    18
        VAS<31
    52
    58
    No statistical analyses for this end point

    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
    75
    75
    Units: mm
    median (inter-quartile range (Q1-Q3))
        Cumulated pain
    50 (19 to 91)
    40 (23 to 81)
    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
    75
    75
    Units: mm
    median (inter-quartile range (Q1-Q3))
        cumulated pain day 0-2 upon ambulation
    60 (26 to 95)
    52 (21 to 94)
    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
    75
    75
    Units: vas (mm)
    median (inter-quartile range (Q1-Q3))
        Cumulated pain day 0-2 upon passive legg raise
    31 (0 to 85)
    14 (0 to 54)
    No statistical analyses for this end point

    Secondary: Cumulted pain day 0-2 during nights

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    End point title
    		 Cumulted pain day 0-2 during nights
    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
    75
    75
    Units: VAS (mm)
    median (inter-quartile range (Q1-Q3))
        Cumulated pain day 0-2 during nights
    49 (16 to 92)
    63 (33 to 90)
    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
    75
    75
    Units: mg/L
    median (inter-quartile range (Q1-Q3))
        CRP 24 hours
    25 (13 to 37)
    19 (12 to 31)
        CRP 48 hours
    22 (12 to 42)
    28 (18 to 41)
    No statistical analyses for this end point

    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
    75
    75
    Units: mg of oral morphine
    median (inter-quartile range (Q1-Q3))
        Day 0-2
    30 (15 to 60)
    38 (18 to 64)
    No statistical analyses for this end point

    Secondary: Cumulated opioid-use day 2-7

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    End point title
    		 Cumulated opioid-use day 2-7
    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
    71
    74
    Units: mg
    median (inter-quartile range (Q1-Q3))
        Day 2-7
    30 (0 to 110)
    20 (0 to 68)
    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 (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 recorded, as accepted in the protocol by the local ethics committee and the Danish authorities (DKMA).
    Serious adverse events
    		 Intervention (High dose, HD) Control (standard/intermediate dose (ID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 75 (9.33%)
    7 / 75 (9.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Need of additional surgery
    Additional description: hip dislocation, fractures and soft-tissue debridement
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Fluid imbalance
    Additional description: Pulmonary edema due to fluid imbalance within 90 days of surgery
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
    Additional description: Suspected DVT without positive findings
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Myasthenia gravis
    Additional description: 1 patient presented with onset of myasthenia gravis within 90 days after surgery.
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Cholecystitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
    Additional description: Admission due to decline in known asthma.
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 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 / 75 (0.00%)
    0 / 75 (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
    For support, Contact us.
    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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