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    Clinical Trial Results:
    Catheter-based peripheral regional anaesthesia after orthopaedic surgery: Comparison of low dose, automated periodic infusions with conventional high dose, continuous infusion, and patient-initiated infusions only. A non-inferiority, randomised, controlled trial.

    Summary
    EudraCT number
    		 2017-002280-18
    Trial protocol
    		 DK  
    Global end of trial date
    21 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Mar 2021
    First version publication date
    27 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FIPRA#3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Anaesthesia and Intensive Care
    Sponsor organisation address
    Dyrehavevej 29, Hillerød, Denmark, 3400
    Public contact
    The Department of Anesthesiology, Nordsjællands Hospital Hillerød, +45 48296680, mhmadsen@gmail.com
    Scientific contact
    The Department of Anesthesiology, Nordsjællands Hospital Hillerød, +45 48296680, mhmadsen@gmail.com
    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 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this trial is to investigate whether a low-dose automated, periodic infusion can produce a similar analgesic effect compared to a conventional, high dose, continuous infusion in catheter-based nerve block treatment for patients undergoing orthopaedic surgery. This is exemplified in three sub-trials on different populations: 1: Patients undergoing major shoulder surgery 2: Patients undergoing foot or ankle surgery 3: Patients undergoing major knee surgery
    Protection of trial subjects
    Post-trial care: Approximately two weeks after surgery an investigator called patients to explore adverse events. Furthermore, 90 days after surgery an investigator did a journal survey to investigate readmissions and potential adverse events. All data presented in future published papers will be anonymized.
    Background therapy
    		 Postoperative pain management Patients were discharged on the day of surgery and instructed to use paracetamol 1 g and ibuprofen 400 mg four times daily. Patients were instructed to release a bolus if they experienced severe pain. LA overdosing was impossible due to the built-in lock-out time. In case of repeated ineffective boluses, patients were instructed to take one tablet of oxycodone 5 mg which could be repeated.
    Evidence for comparator
    		 The comparator, being conventional continuous infusions of local anaesthestic through peripheral nerve catheters, are the standard treatment in current postoperative pain management. There is solid evidence of pain relief when used.
    Actual start date of recruitment
    01 Sep 2017
    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: 197
    Worldwide total number of subjects
    197
    EEA total number of subjects
    197
    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)
    119
    From 65 to 84 years
    78
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from September 2017 to January 2019 at Nordsjællands and Bispebjerg University Hospitals.

    Pre-assignment
    Screening details
    		 All patients who were planned to have elective surgery of the fore- and mid-foot or to undergo total knee arthroplasty.

    Period 1
    Period 1 title
    Postoperative days 1-4 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor
    Blinding implementation details
    Opaque envelopes ensured allocation concealment. Programming and the display of the infusion pumps were blinded to investigators as well as to participants. Also, the delivery methods of the interventions not delivering programmed intermittent boluses (i.e. continuous infusion and boluses on-demand only) were programmed with a sham bolus of 0.1ml every 8th hour to further mask the intervention.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Continuous infusion - FOOT
    Arm description
    		 A basal infusion of ropivacaine of 6 mL/h with the possibility of patient controlled catheter based bolus of local anaesthesia
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ropivacaine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Perineural use
    Dosage and administration details
    6 ml / h of ropivacaine 0.2% with patient controlled bolus 10 ml (foot) or 15 ml (knee) at most every 4th hour.

    Arm title
    		 Intermittent bolus - FOOT
    Arm description
    		 A programmed intermittent bolus of ropivacaine 10 mL every 8 hour
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ropivacaine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Perineural use
    Dosage and administration details
    A programmed intermittent bolus of 10 ml every 8 hour (foot) or 15 ml every 10 hour (knee) with a optional patient controlled bolus of 10 of 15 ml (foot or knee) at most every 4th hour.

    Arm title
    		 Bolus on-demand only - FOOT
    Arm description
    		 No planned treatment but an optional patient-controlled bolus of ropivacaine 10 mL every 4th hour (lockout period) if needed.
    Arm type
    		 Active control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Continuous infusion - KNEE
    Arm description
    		 Continuous infusion of ropivacaine, 6 mL/hour and optional patient-controlled bolus of 15 mL every 6th hour if needed.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ropivacaine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Perineural use
    Dosage and administration details
    6 ml / h of ropivacaine 0.2% with patient controlled bolus 10 ml (foot) or 15 ml (knee) at most every 4th hour.

    Arm title
    		 Intermittent bolus - KNEE
    Arm description
    		 Programmed intermittent bolus of ropivacaine 15 mL every 12th hour and optional bolus on demand every 6th hour if needed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ropivacaine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Perineural use
    Dosage and administration details
    6 ml / h of ropivacaine 0.2% with patient controlled bolus 10 ml (foot) or 15 ml (knee) at most every 4th hour.

    Arm title
    		 Bolus on-demand only - KNEE
    Arm description
    		 No basal treatment but optional bolus on-demand of 15 mL of ropivacaine every 6th hour if needed.
    Arm type
    		 Active control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Continuous infusion - FOOT Intermittent bolus - FOOT Bolus on-demand only - FOOT Continuous infusion - KNEE Intermittent bolus - KNEE Bolus on-demand only - KNEE
    Started
    29
    30
    27
    39
    35
    37
    Completed
    27
    27
    27
    27
    27
    27
    Not completed
    2
    3
    0
    12
    8
    10
         Consent withdrawn by subject
    1
    1
    -
    5
    4
    5
         Adverse event, non-fatal
    -
    -
    -
    2
    1
    1
         Catheter failure
    1
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    2
    -
    5
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Postoperative days 1-4
    Reporting group description
    		 -

    Reporting group values
    		 Postoperative days 1-4 Total
    Number of subjects
    		 197 197
    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)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 84 84
        From 65-84 years
    		 111 111
        85 years and over
    		 2 2
    Age continuous
    Units: years
        median (standard deviation)
    		 69 ± 8 -
    Gender categorical
    Units: Subjects
        Female
    		 138 138
        Male
    		 59 59
    Subject analysis sets

    Subject analysis set title
    KNEE
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients undergoing elective total knee arthroplasty

    Subject analysis set title
    FOOT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients undergoing elective fore- and midfoot surgery.

    Subject analysis sets values
    		 KNEE FOOT
    Number of subjects
    111
    86
    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)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    23
    61
        From 65-84 years
    86
    25
        85 years and over
    2
    0
    Age continuous
    Units: years
        median (standard deviation)
    70 ± 8
    57 ± 14
    Gender categorical
    Units: Subjects
        Female
    69
    66
        Male
    42
    15

    End points

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    End points reporting groups
    Reporting group title
    Continuous infusion - FOOT
    Reporting group description
    		 A basal infusion of ropivacaine of 6 mL/h with the possibility of patient controlled catheter based bolus of local anaesthesia

    Reporting group title
    Intermittent bolus - FOOT
    Reporting group description
    		 A programmed intermittent bolus of ropivacaine 10 mL every 8 hour

    Reporting group title
    Bolus on-demand only - FOOT
    Reporting group description
    		 No planned treatment but an optional patient-controlled bolus of ropivacaine 10 mL every 4th hour (lockout period) if needed.

    Reporting group title
    Continuous infusion - KNEE
    Reporting group description
    		 Continuous infusion of ropivacaine, 6 mL/hour and optional patient-controlled bolus of 15 mL every 6th hour if needed.

    Reporting group title
    Intermittent bolus - KNEE
    Reporting group description
    		 Programmed intermittent bolus of ropivacaine 15 mL every 12th hour and optional bolus on demand every 6th hour if needed.

    Reporting group title
    Bolus on-demand only - KNEE
    Reporting group description
    		 No basal treatment but optional bolus on-demand of 15 mL of ropivacaine every 6th hour if needed.

    Subject analysis set title
    KNEE
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients undergoing elective total knee arthroplasty

    Subject analysis set title
    FOOT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients undergoing elective fore- and midfoot surgery.

    Primary: Pain

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    End point title
    		 Pain
    End point description
    Pain self-reported on the Visual Analogue Scale, 0-100mm, on 18 specified time points. Measured as Area Under the Curve.
    End point type
    Primary
    End point timeframe
    Postoperative days 1-4
    End point values
    		 Continuous infusion - FOOT Intermittent bolus - FOOT Bolus on-demand only - FOOT Continuous infusion - KNEE Intermittent bolus - KNEE Bolus on-demand only - KNEE KNEE FOOT
    Number of subjects analysed
    27
    27
    27
    27
    27
    27
    81
    54
    Units: millimeter(s)
        arithmetic mean (confidence interval 95%)
    1206 (749 to 1663)
    1621 (1143 to 2099)
    1583 (1120 to 2046)
    1974 (1350 to 2482)
    1833 (1020 to 2670)
    2621 (1450 to 3100)
    141 (-692 to 874)
    -416 (-1076 to 244)
    Statistical analysis title
    		 Analysis of primary endpoint
    Statistical analysis description
    Intergroup comparison of the two primary intervention groups (intervention vs. comparator) was done by student's t test.
    Comparison groups
    Intermittent bolus - FOOT v Continuous infusion - FOOT
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    1440
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1050
         upper limit
    		 1830
    Variability estimate
    Standard deviation
    Dispersion value
    1800

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately two weeks after surgery an investigator called patients to explore adverse events. Furthermore, 90 days after surgery an investigator did a journal survey to investigate readmissions and potential adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CONSORT
    Dictionary version
    2010
    Reporting groups
    Reporting group title
    Overall trial cohort
    Reporting group description
    		 -

    Serious adverse events
    		 Overall trial cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 197 (0.51%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Infection at catheter site
         subjects affected / exposed
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall trial cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 197 (2.03%)
    Product issues
    Perineural catheter dysfunction or leak
         subjects affected / exposed
    4 / 197 (2.03%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2018
    Because of loss to follow-up we did not meet the expected inclusion rate and asked the appropriate authorities for trial period extension.

    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.
    None reported
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