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    Clinical Trial Results:
    Perineural Local Anaesthetic Catheter aftEr Major lowEr limb amputatioN Trial (PLACEMENT)

    Summary
    EudraCT number
    		 2016-003544-37
    Trial protocol
    		 GB  
    Global end of trial date
    31 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jun 2020
    First version publication date
    11 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ABUHB/01/0816/1
    Additional study identifiers
    ISRCTN number
    		 ISRCTN85710690
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aneurin Bevan Univeristy Health Board
    Sponsor organisation address
    Cardiff Road, Newport, United Kingdom, NP20 2UB
    Public contact
    Trial Manager, Centre for Trials Research, Cardiff University, 02920 687609, PLACEMENT-Trial@cardiff.ac.uk
    Scientific contact
    Trial Manager, Centre for Trials Research, Cardiff University, 02920 687609, PLACEMENT-Trial@cardiff.ac.uk
    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
    22 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal research question is whether it is feasible to run a pragmatic randomised controlled trial to investigate the effect of a perineural catheter (PNC) use plus usual care compared to usual care alone on post-operative pain.
    Protection of trial subjects
    TSC took on the role of IDMC, PID
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jan 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
    United Kingdom: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    14
    From 65 to 84 years
    34
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was recruited on 06.02.2017 and the final patient on 15.11.2017. Follow up continued for 6 months post-surgery.

    Pre-assignment
    Screening details
    		 Patients listed for major lower limb amputation will be screened by members of the clinical care team against the above inclusion/exclusion criteria. Those who are considered potentially suitable for inclusion will be approached and provided with a Patient Information Sheet (PIS) by a member of the clinical care team.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Usual Care
    Arm description
    		 Best available standard care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Peri-neural catheter
    Arm description
    		 Received peri-neural catheter to infuse local anaesthesia into amputation area intra-operatively
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levobupivacaine hydrochloride 0.125%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Perineural use
    Dosage and administration details
    The local anaesthetic used in this trial is Levobupivacaine hydrochloride 0.125%, which will be administered via the above described epidural catheter and infusion device at a rate of 2-12 ml per hour (2.5-15 mg/hr).

    Number of subjects in period 1
    		Usual Care Peri-neural catheter
    Started
    27
    23
    Completed
    26
    23
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    		 Best available standard care

    Reporting group title
    Peri-neural catheter
    Reporting group description
    		 Received peri-neural catheter to infuse local anaesthesia into amputation area intra-operatively

    Reporting group values
    		 Usual Care Peri-neural catheter Total
    Number of subjects
    		 27 23 50
    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
    Units: years
        arithmetic mean (standard deviation)
    		 69.9 ( 10.20 ) 69.7 ( 9.99 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 4 10
        Male
    		 21 19 40
    Level of amputation
    Units: Subjects
        Below knee
    		 15 16 31
        Above knee
    		 12 7 19
    Site
    Units: Subjects
        Royal Gwent Hospital
    		 11 9 20
        Morriston Hospital
    		 16 14 30
    Opioid Use
    Units: Morphine Equivalance Scale
        median (inter-quartile range (Q1-Q3))
    		 5.3 (1.8 to 23.7) 4.6 (0.0 to 18.0) -
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised

    Subject analysis sets values
    		 ITT
    Number of subjects
    50
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.8 ( 10.00 )
    Gender categorical
    Units: Subjects
        Female
    10
        Male
    40
    Level of amputation
    Units: Subjects
        Below knee
    31
        Above knee
    19
    Site
    Units: Subjects
        Royal Gwent Hospital
    20
        Morriston Hospital
    30
    Opioid Use
    Units: Morphine Equivalance Scale
        median (inter-quartile range (Q1-Q3))
    4.6 (0.0 to 18.0)

    End points

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    End points reporting groups
    Reporting group title
    Usual Care
    Reporting group description
    		 Best available standard care

    Reporting group title
    Peri-neural catheter
    Reporting group description
    		 Received peri-neural catheter to infuse local anaesthesia into amputation area intra-operatively

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised

    Primary: Provide data on alternative primary outcome of those included

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    End point title
    		 Provide data on alternative primary outcome of those included
    End point description
    Definition of alternative primary outcome: modal value of potential 17 post surgery pain scores. These scores are a combination of patient-reported 11-point pain scores converted to 4-point and, where the patient-reported version is not available, nurse-reported 4-point pain scores. The modal calculation is only made if 9 or more values are available. This alternative was calculated (as defined in the SAP) because the original primary outcome (using just patient-reported 11-point pain scores) was only available for 34/49 (62.1), which was less than the pre-specified 90%. A 'traffic light' system will be used to identify levels deemed acceptable (green), possibly acceptable with discussion and amendments (amber) and unacceptable (red). These criteria are: • For the proportion of randomised patients that provide data for the primary outcome: o greater than 0.9 - green; o 0.9 to 0.6 - amber; o less than 0.6 - red.
    End point type
    Primary
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    26
    23
    49 [1]
    Units: Subjects
        No
    3
    1
    4
        Yes
    23
    22
    45
    Notes
    [1] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) that had no ability to provide
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Peri-neural catheter v Usual Care v ITT
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    91.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 80.81
         upper limit
    		 96.78

    Primary: Provide data on original primary outcome of those included

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    End point title
    		 Provide data on original primary outcome of those included
    End point description
    Definition of original primary outcome: mean value of potential 17 post surgery pain scores. These scores are patient-reported 11-point pain scores. A 'traffic light' system will be used to identify levels deemed acceptable (green), possibly acceptable with discussion and amendments (amber) and unacceptable (red). These criteria are: • For the proportion of randomised patients that provide data for the primary outcome: o greater than 0.9 - green; o 0.9 to 0.6 - amber; o less than 0.6 - red.
    End point type
    Primary
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    26
    23
    49 [2]
    Units: Subjects
        No
    8
    7
    15
        Yes
    18
    16
    34
    Notes
    [2] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) that had no ability to provide
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    69.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 55.47
         upper limit
    		 80.48

    Primary: Provide data on Chronic Stump Pain of those reaching 6 weeks

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    End point title
    		 Provide data on Chronic Stump Pain of those reaching 6 weeks
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    23
    22
    45 [3]
    Units: Subjects
        No
    11
    5
    16
        Yes
    12
    17
    29
    Notes
    [3] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 4 deceased before 6 weeks
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    64.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 49.84
         upper limit
    		 76.78

    Primary: Provide data on Phantom Limb Pain of those reaching 6 weeks

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    End point title
    		 Provide data on Phantom Limb Pain of those reaching 6 weeks
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    23
    22
    45 [4]
    Units: Subjects
        No
    11
    7
    18
        Yes
    12
    15
    27
    Notes
    [4] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 4 deceased before 6 weeks
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    60
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 45.45
         upper limit
    		 72.98

    Primary: Provide data on Chronic Stump Pain of those reaching 6 months

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    End point title
    		 Provide data on Chronic Stump Pain of those reaching 6 months
    End point description
    End point type
    Primary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    21
    20
    41 [5]
    Units: Subjects
        No
    12
    11
    23
        Yes
    9
    9
    18
    Notes
    [5] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 8 deceased before 6 months
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    43.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.89
         upper limit
    		 58.96

    Primary: Provide data on Phantom Limb Pain of those reaching 6 months

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    End point title
    		 Provide data on Phantom Limb Pain of those reaching 6 months
    End point description
    End point type
    Primary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    21
    20
    41 [6]
    Units: Subjects
        No
    14
    13
    27
        Yes
    7
    7
    14
    Notes
    [6] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 8 deceased before 6 months
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    34.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.56
         upper limit
    		 49.45

    Primary: Alternative primary outcome

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    End point title
    		 Alternative primary outcome
    End point description
    End point type
    Primary
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    23 [7]
    22 [8]
    45 [9]
    Units: Subjects
        None
    11
    14
    25
        Mild
    6
    5
    11
        Moderate
    3
    2
    5
        Severe
    3
    1
    4
    Notes
    [7] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 3 missing alternative primary
    [8] - All randomised minus 1 missing alternative primary
    [9] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 4 missing alternative primary
    Statistical analysis title
    		 Ordinal logistic modelling
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.376
    Method
    		 Regression, ordinal logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.571
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.165
         upper limit
    		 1.975
    Notes
    [10] - Exploratory analysis of potential future primary outcome. The analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates. BMI was planned to be included but was not collected fully. An original regional Anaesthesia variable was to be included as a covariate but a new variable with merged categories had to be used instead as only 1 subject received Continuous infusion.

    Secondary: HADS Anxiety Score at 6 weeks

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    End point title
    		 HADS Anxiety Score at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    12
    15
    Units: HADS Scale
        arithmetic mean (standard deviation)
    4.6 ( 4.50 )
    5.7 ( 5.56 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.291
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.835
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.244
         upper limit
    		 1.574
    Notes
    [11] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: HADS Anxiety Score at 6 months

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    End point title
    		 HADS Anxiety Score at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    8
    7
    Units: HADS Anxiety Scale
        arithmetic mean (standard deviation)
    7.0 ( 6.68 )
    7.6 ( 4.28 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.978
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.83
         upper limit
    		 7.609
    Notes
    [12] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: HADS Depression Score at 6 weeks

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    End point title
    		 HADS Depression Score at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    13
    16
    Units: HADS Depression Scale
        arithmetic mean (standard deviation)
    7.2 ( 5.79 )
    5.8 ( 3.55 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.155
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.912
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.549
         upper limit
    		 0.725
    Notes
    [13] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: HADS Depression Score at 6 months

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    End point title
    		 HADS Depression Score at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    8
    7
    Units: HADS Depression Scale
        arithmetic mean (standard deviation)
    7.9 ( 6.60 )
    8.0 ( 2.89 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.411
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.211
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.099
         upper limit
    		 1.676
    Notes
    [14] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: EQ-5D Health today VAS at 6 weeks

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    End point title
    		 EQ-5D Health today VAS at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    13
    17
    Units: EQ-5D VAS
        arithmetic mean (standard deviation)
    66.2 ( 23.99 )
    70.1 ( 23.99 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.347
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.977
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.558
         upper limit
    		 21.512
    Notes
    [15] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: EQ-5D Health today VAS at 6 months

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    End point title
    		 EQ-5D Health today VAS at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    8
    8
    Units: EQ-5D VAS
        arithmetic mean (standard deviation)
    60.6 ( 25.42 )
    71.9 ( 11.63 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.148
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.705
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.459
         upper limit
    		 22.87
    Notes
    [16] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Natural log of EQ-5D-5L Crosswalk to EQ-5D-3L at 6 weeks

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    End point title
    		 Natural log of EQ-5D-5L Crosswalk to EQ-5D-3L at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    12
    17
    Units: Natural log scale
        arithmetic mean (standard deviation)
    0.1365 ( 0.31765 )
    0.0619 ( 0.16781 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.376
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.067
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.215
         upper limit
    		 0.081
    Notes
    [17] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Natural log of EQ-5D-5L Crosswalk to EQ-5D-3L at 6 months

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    End point title
    		 Natural log of EQ-5D-5L Crosswalk to EQ-5D-3L at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    8
    9
    Units: Natural log scale
        arithmetic mean (standard deviation)
    0.1644 ( 0.23361 )
    0.0076 ( 0.18991 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.311
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.459
         upper limit
    		 -0.163
    Notes
    [18] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Treatment failure

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    End point title
    		 Treatment failure
    End point description
    1 required emergency surgery so the baseline pain scale (a covariate in the model) was not collected and thus only 48 are reported in this analysis
    End point type
    Secondary
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    25
    23
    Units: Subjects
        No
    3
    6
        Yes
    22
    17
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.376
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.571
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.165
         upper limit
    		 1.975
    Notes
    [19] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Surgical site infection

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    End point title
    		 Surgical site infection
    End point description
    End point type
    Secondary
    End point timeframe
    At discharge
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    23
    23
    Units: Subjects
        No
    21
    22
        Yes
    2
    1
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.655
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.554
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 7.369
    Notes
    [20] - Exploratory analysis. Analysis undertaken with site, level of amputation, age, opioid use at baseline and history of diabetes mellitus. NB. Estimate made without gender and (Additional Regional Anaesthesia (Variable) covariates, as co-linear.

    Secondary: Nausea and vomiting

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    End point title
    		 Nausea and vomiting
    End point description
    End point type
    Secondary
    End point timeframe
    At discharge
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    23
    23
    Units: Subjects
        No
    17
    21
        Yes
    6
    2
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.127
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.249
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 1.487
    Notes
    [21] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Chronic Stump Pain at 6 weeks

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    End point title
    		 Chronic Stump Pain at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    12
    15
    Units: Subjects
        Absent
    8
    14
        Present
    4
    3
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.332
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.228
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.012
         upper limit
    		 4.535
    Notes
    [22] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Phantom Limb Pain at 6 weeks

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    End point title
    		 Phantom Limb Pain at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    12
    15
    Units: Subjects
        Absent
    7
    11
        Present
    5
    4
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.12
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.158
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.015
         upper limit
    		 1.623
    Notes
    [23] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Chronic Stump Pain at 6 months

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    End point title
    		 Chronic Stump Pain at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    9
    9
    Units: Subjects
        Absent
    6
    7
        Present
    3
    2
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.207
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.137
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.006
         upper limit
    		 3.015
    Notes
    [24] - Exploratory analysis. Analysis undertaken with site, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates. NB. Estimate made without gender covariate, as co-linear.

    Secondary: Phantom Limb Pain at 6 months

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    End point title
    		 Phantom Limb Pain at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    7
    7
    Units: Subjects
        Absent
    5
    4
        Present
    2
    3
    Statistical analysis title
    		 Odds ratio
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.56
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.286
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.142
         upper limit
    		 36.808
    Notes
    [25] - Exploratory analysis. Analysis undertaken with gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates. NB. Estimate made without Site covariate, else no convergence

    Secondary: Natural log of OBAS

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    End point title
    		 Natural log of OBAS
    End point description
    End point type
    Secondary
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    24
    23
    Units: Natural log scale
        arithmetic mean (standard deviation)
    1.3 ( 0.57 )
    1.2 ( 0.63 )
    Statistical analysis title
    		 Difference in means
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.16
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.528
         upper limit
    		 0.087
    Notes
    [26] - Exploratory analysis. Analysis undertaken with site, gender, level of amputation, age, opioid use at baseline, history of diabetes mellitus and (additional) regional Anaesthesia (variable) as covariates.

    Secondary: Successful identification of nerve

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    End point title
    		 Successful identification of nerve [27]
    End point description
    End point type
    Secondary
    End point timeframe
    At surgery
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is only relevant to the Peri-neural Catheter arm.
    End point values
    		 Peri-neural catheter
    Number of subjects analysed
    23
    Units: Subjects
        No
    0
        Yes
    23
    No statistical analyses for this end point

    Secondary: Successful placement of Peri-neural Catheter

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    End point title
    		 Successful placement of Peri-neural Catheter [28]
    End point description
    End point type
    Secondary
    End point timeframe
    At surgery
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is only relevant to the Peri-neural Catheter arm.
    End point values
    		 Peri-neural catheter
    Number of subjects analysed
    23
    Units: Subjects
        No
    0
        Yes
    23
    No statistical analyses for this end point

    Secondary: S-LANSS at 5 days

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    End point title
    		 S-LANSS at 5 days
    End point description
    End point type
    Secondary
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    21
    20
    Units: S-LANSS Scale
        median (inter-quartile range (Q1-Q3))
    12.0 (3.0 to 14.0)
    6.5 (0.0 to 13.5)
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.331
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [29] - Exploratory analysis.

    Secondary: S-LANSS at 6 weeks

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    End point title
    		 S-LANSS at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    12
    16
    Units: S-LANSS Scale
        median (inter-quartile range (Q1-Q3))
    0.0 (0.0 to 6.0)
    5.0 (2.0 to 11.0)
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.159 [31]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [30] - Exploratory analysis.
    [31] - Exact, rather than asymptotic, p-value displayed based on algorithm of Dineen and Blakesley

    Secondary: S-LANSS at 6 months

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    End point title
    		 S-LANSS at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    8
    8
    Units: S-LANSS Scale
        median (inter-quartile range (Q1-Q3))
    9.0 (1.0 to 13.0)
    10 (2.5 to 16.5)
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.721 [33]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [32] - Exploratory analysis.
    [33] - Exact, rather than asymptotic, p-value based on algorithm of Dineen and Blakesley

    Secondary: Opioid Use

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    End point title
    		 Opioid Use
    End point description
    End point type
    Secondary
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter
    Number of subjects analysed
    25
    23
    Units: Equivalent Morphine Use
        median (inter-quartile range (Q1-Q3))
    12.2 (7.0 to 22.5)
    8.0 (3.0 to 21.0)
    Statistical analysis title
    		 Mann-Whitney U test
    Comparison groups
    Usual Care v Peri-neural catheter
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 0.302
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [34] - Exploratory analysis.

    Other pre-specified: Provide data on Treatment Failure

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    End point title
    		 Provide data on Treatment Failure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    26
    23
    49 [35]
    Units: Subjects
        No
    0
    0
    0
        Yes
    26
    23
    49
    Notes
    [35] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) that had no ability to provide
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 92.73
         upper limit
    		 100

    Other pre-specified: Provide data on OBAS

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    End point title
    		 Provide data on OBAS
    End point description
    End point type
    Other pre-specified
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    26
    23
    49 [36]
    Units: Subjects
        No
    2
    0
    2
        Yes
    24
    23
    47
    Notes
    [36] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) that had no ability to provide
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    95.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 86.29
         upper limit
    		 98.87

    Other pre-specified: Provide data on Opioid Use

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    End point title
    		 Provide data on Opioid Use
    End point description
    End point type
    Other pre-specified
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    26
    23
    49 [37]
    Units: Subjects
        No
    1
    0
    1
        Yes
    25
    23
    48
    Notes
    [37] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) that had no ability to provide
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Peri-neural catheter v Usual Care v ITT
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    97.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 89.31
         upper limit
    		 99.64

    Other pre-specified: Provide data on S-LANSS at Day 5

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    End point title
    		 Provide data on S-LANSS at Day 5
    End point description
    End point type
    Other pre-specified
    End point timeframe
    5 days post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    26
    23
    49 [38]
    Units: Subjects
        No
    5
    3
    8
        Yes
    21
    29
    41
    Notes
    [38] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) that had no ability to provide
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    83.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 70.96
         upper limit
    		 91.49

    Other pre-specified: Provide data on Clavien-Dindo

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    End point title
    		 Provide data on Clavien-Dindo
    End point description
    Clavien-Dindo used to assess Nausea and vomiting, and Surgical Site Infection outcomes
    End point type
    Other pre-specified
    End point timeframe
    At discharge
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    26
    23
    49 [39]
    Units: Subjects
        No
    3
    0
    3
        Yes
    23
    23
    46
    Notes
    [39] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) that had no ability to provide
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    93.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 83.48
         upper limit
    		 97.9

    Other pre-specified: Provide data on S-LANSS at 6 weeks

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    End point title
    		 Provide data on S-LANSS at 6 weeks
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    23
    22
    45 [40]
    Units: Subjects
        No
    11
    6
    17
        Yes
    12
    16
    28
    Notes
    [40] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 4 deceased before 6 weeks
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    62.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47.63
         upper limit
    		 74.89

    Other pre-specified: Provide data on S-LANSS at 6 months

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    End point title
    		 Provide data on S-LANSS at 6 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    21
    20
    41 [41]
    Units: Subjects
        No
    13
    12
    25
        Yes
    8
    8
    16
    Notes
    [41] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 8 deceased before 6 months
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    39.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.66
         upper limit
    		 54.27

    Other pre-specified: Provide data on HADS at 6 weeks

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    End point title
    		 Provide data on HADS at 6 weeks
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    23
    22
    45 [42]
    Units: Subjects
        No
    10
    5
    15
        Yes
    13
    17
    30
    Notes
    [42] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 4 deceased before 6 weeks
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    66.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 52.07
         upper limit
    		 78.64

    Other pre-specified: Provide data on HADS at 6 months

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    End point title
    		 Provide data on HADS at 6 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    21
    20
    41 [43]
    Units: Subjects
        No
    12
    12
    24
        Yes
    9
    8
    17
    Notes
    [43] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 8 deceased before 6 months
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    41.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 27.76
         upper limit
    		 56.63

    Other pre-specified: Provide data on EQ-5D at 6 weeks

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    End point title
    		 Provide data on EQ-5D at 6 weeks
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    23
    22
    45 [44]
    Units: Subjects
        No
    11
    5
    16
        Yes
    12
    17
    29
    Notes
    [44] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 4 deceased before 6 weeks
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    64.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 49.84
         upper limit
    		 76.78

    Other pre-specified: Provide data on EQ-5D at 6 months

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    End point title
    		 Provide data on EQ-5D at 6 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 months post-surgery
    End point values
    		 Usual Care Peri-neural catheter ITT
    Number of subjects analysed
    21
    20
    41 [45]
    Units: Subjects
        No
    12
    11
    23
        Yes
    9
    9
    18
    Notes
    [45] - All randomised minus 1 peri-operative exclusion (SAE - Non-fatal) and 8 deceased before 6 months
    Statistical analysis title
    		 95% Confidence Interval (Wilson's Method)
    Comparison groups
    Usual Care v Peri-neural catheter v ITT
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage
    Point estimate
    43.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.89
         upper limit
    		 58.96

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs reported from time the patient goes into theatre, throughout the treatment period up to, and including 7 days post-operation. Serious adverse reactions (such as long term side effects of trial treatment) reported until the end of follow up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.02
    Reporting groups
    Reporting group title
    Usual care
    Reporting group description
    		 -

    Reporting group title
    Peri-neural catheter (Levobupivacaine)
    Reporting group description
    		 -

    Serious adverse events
    		 Usual care Peri-neural catheter (Levobupivacaine)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 27 (22.22%)
    3 / 23 (13.04%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Opioid toxicity
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    (L) MCA territory ischemic stroke
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arterial bleed
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    fractured neck of femur
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 23 (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
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stump infection
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Usual care Peri-neural catheter (Levobupivacaine)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 27 (25.93%)
    9 / 23 (39.13%)
    Injury, poisoning and procedural complications
    Other - Falls & wound dehiscence
    Additional description: fell on stump- slight bleeding, fell on stump - wound dehiscence, fall - no injuries, wound dehiscence, above knee amputation non-viable stump, non healing stump with minimal blood loss, fall - small cut to head, pressure ulcer, death.
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 23 (13.04%)
         occurrences all number
    5
    4
    Cardiac disorders
    Cardiopulmonary
    Additional description: Pleural drain, hypotensive
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Nervous system disorders
    Neurologic
    Additional description: Stroke
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Bleeding/hematoma
    Additional description: Blood transfusion, blood transfusion in theatre, blood transfusion post op, Low HB - blood transfusion, PR bleeding, blood loss.
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    6 / 27 (22.22%)
    3 / 23 (13.04%)
         occurrences all number
    7
    3
    Gastrointestinal disorders
    Nausea and vomiting
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    6 / 27 (22.22%)
    2 / 23 (8.70%)
         occurrences all number
    6
    2
    Skin and subcutaneous tissue disorders
    Other - Rash
    Additional description: Rash - iliac fossa
    alternative dictionary used: Clavien Dindo system 1
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Pain
    Additional description: Pain
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Endocrine disorders
    Other - Hypoglycaemia
    Additional description: Hypoglycaemic event
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    Infections and infestations
    Infection
    Additional description: Hospital acquired pneumonia, UTI, septic from UTI with cardiovascular and renal failure, recurrent UTI, wound infection, urosepsis
    alternative dictionary used: Clavien-Dindo system 1
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 23 (13.04%)
         occurrences all number
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jul 2017
    Substantial amendment to consent form. Added permission for a nominated alternative contact person to be contacted if a participant cannot be reached for their 6 week and 6 month follow ups. Substantial amendment - addition of follow up letter. Sent out if a participant cannot be reached for their follow ups. It gives options for completing the follow up questionnaires by post, return to the research nurse at next clinic appointment, or complete at home and research nurse will call to record answers over the telephone. This letter has been created to improve follow up rates.
    16 Jan 2018
    Addition of peri-operative risk modelling work. An analysis of national registry data to allow better quantification of peri-operative risk for patients undergoing major lower limb amputation.
    20 Feb 2018
    Addition of a consent form and participant information sheet for the qualitative study for relatives. To be used if both the patient decides they would like the relative present, and the relative decides they wish to contribute in the qualitative interviews. Also, addition of the Healthcare Professional consent to contact form to be used for Healthcare Professional details to be passed onto the qualitative researcher so they can contact the Healthcare Professional about participating in the qualitative interviews for the process evaluation.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31719071
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