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    Clinical Trial Results:
    A placebo controlled randomised trial of intravenous lidocaine in accelerating gastrointestinal recovery after colorectal surgery

    Summary
    EudraCT number
    		 2017-003835-12
    Trial protocol
    		 GB  
    Global end of trial date
    10 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2025
    First version publication date
    02 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC17067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Edinburgh & NHS Lothian
    Sponsor organisation address
    47 Little France Crescent, Edinburgh , United Kingdom, EH16 4TJ
    Public contact
    Seonaidh Cotton, The University of Aberdeen, s.c.cotton@abdn.ac.uk
    Scientific contact
    Thenmalar Vadiveloo, The University of Aberdeen, thenmalar.vadiveloo@abdn.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
    18 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Apr 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim is an effectiveness analysis to measure whether intravenous lidocaine (given at time of surgery) achieves faster return of gut function for more patients after colorectal surgery. The primary outcome will be the proportion of randomised subjects compared between IV lidocaine and placebo that have achieved return of gut function at 72 hours after their surgery. This will be measured by ‘GI-3 recovery’ -an endpoint defined as achievement of both of the following two events: tolerating diet (defined as ingestion of food and drink without significant nausea or vomiting for 3 consecutive meals) and passage of flatus OR stool (whichever comes first).
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 The comparator is a placebo, which is a 0.9% sterile Sodium Chloride solution for injection. It is a clear and colourless solution. The placebo will appear identical to the IMP.
    Actual start date of recruitment
    14 Aug 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
    United Kingdom: 557
    Worldwide total number of subjects
    557
    EEA total number of subjects
    0
    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)
    238
    From 65 to 84 years
    303
    85 years and over
    16

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were identified by site study teams and a member of the usual care team approached patients about study participation at existing points of contact prior to surgery. Patients who wished to participate provided written, informed consent. Participants were recruited between 14th August 2018 and 11th April 2023.

    Pre-assignment
    Screening details
    		 In total, 1145 patients were identified/screened, 539 were excluded, 16 patients were recruited to the open study and 590 were consented and randomly assigned to the main study. There were 33 post-randomisation exclusions.

    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, Assessor
    Blinding implementation details
    Participants, medical staff and study staff/outcome assessors were all blinded in this study. Both study drug and placebo were clear colourless liquids and were packaged in identical containers. Upon randomisation the participant was allocated a unique participant study number and assigned a numbered participant pack. Randomisation triggered a notification email to pharmacy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IV Lidocaine
    Arm description
    		 Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride
    Arm type
    		 Experimental

    Investigational medicinal product name
    IV Lidocaine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The patient received an intravenous bolus of study drug at induction of anaesthesia (1.5mg/kg ideal body weight) given over 20 minutes followed by intravenous infusion of 1.5 mg/hour/kg ideal body weight with a maximum rate of 120mg/hour (6ml/hour) for a minimum of 6 hours up to a maximum of 12 hours. Calculation of the correct infusion rate and administration of the study drug/placebo was undertaken by the responsible anaesthetist for the operation. Exemplar dose calculation tables were provided in the study protocol. Ideal body weight was used rather than actual body weight to prevent the possibility of toxicity by exceeding the upper therapeutic threshold of lidocaine in very overweight patients.

    Arm title
    		 Placebo
    Arm description
    		 0.9% sterile Sodium Chloride solution for injection.
    Arm type
    		 Placebo

    Investigational medicinal product name
    IV Lidocaine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The patient received an intravenous bolus of study drug at induction of anaesthesia (1.5mg/kg ideal body weight) given over 20 minutes followed by intravenous infusion of 1.5 mg/hour/kg ideal body weight with a maximum rate of 120mg/hour (6ml/hour) for a minimum of 6 hours up to a maximum of 12 hours. Calculation of the correct infusion rate and administration of the study drug/placebo was undertaken by the responsible anaesthetist for the operation. Exemplar dose calculation tables were provided in the study protocol. Ideal body weight was used rather than actual body weight to prevent the possibility of toxicity by exceeding the upper therapeutic threshold of lidocaine in very overweight patients.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Infusion same as IV lidoacaine arm

    Number of subjects in period 1
    		IV Lidocaine Placebo
    Started
    279
    278
    Completed
    279
    278

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IV Lidocaine
    Reporting group description
    		 Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride

    Reporting group title
    Placebo
    Reporting group description
    		 0.9% sterile Sodium Chloride solution for injection.

    Reporting group values
    		 IV Lidocaine Placebo Total
    Number of subjects
    		 279 278 557
    Age categorical
    Age was collected at baseline and reported as n(%) for each category
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults (50-74 years)
    		 198 198 396
        Adults (18-49 years)
    		 18 19 37
        Adults (75 and above)
    		 63 61 124
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.9 ( 11.0 ) 66.5 ( 10.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 122 127 249
        Male
    		 157 151 308
    Current smoking status
    Units: Subjects
        Yes
    		 24 26 50
        No
    		 255 251 506
        Missing
    		 0 1 1
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28.0 ( 5.6 ) 28.0 ( 5.4 ) -
    EQ-5D-5L
    Total score for EQ-5D-5L
    Units: Score
        arithmetic mean (standard deviation)
    		 0.833 ( 0.146 ) 0.825 ( 0.168 ) -
    EQ-5D-5L - Visual analogue scale
    Units: Score
        arithmetic mean (standard deviation)
    		 77.7 ( 18.3 ) 78.1 ( 18.1 ) -
    Overall Benefit of Analgesia Score
    Units: Score
        arithmetic mean (standard deviation)
    		 2.62 ( 2.87 ) 2.53 ( 2.69 ) -
    Quality of recovery-15
    Units: Score
        arithmetic mean (standard deviation)
    		 96.67 ( 11.09 ) 96.11 ( 12.15 ) -

    End points

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    End points reporting groups
    Reporting group title
    IV Lidocaine
    Reporting group description
    		 Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride

    Reporting group title
    Placebo
    Reporting group description
    		 0.9% sterile Sodium Chloride solution for injection.

    Primary: Proportion of randomised subjects that have achieved return of gut function at 72 hours postoperatively

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    End point title
    		 Proportion of randomised subjects that have achieved return of gut function at 72 hours postoperatively
    End point description
    Return of gut function was measured by 'GI-3' - composite endpoint defined as achievement of both of the following two events: tolerating diet (defined as ingestion of food and drink without significant nausea or vomiting for 3 consecutive meals) and passage of flatus OR stool (whichever comes first).
    End point type
    Primary
    End point timeframe
    72 hours post-operative
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        Achieved GI-3
    160
    164
        Did not achieve GI-3
    119
    114
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    The primary outcome was analysed using a generalised linear model with a logit link function adjusted for the minimisation factors using fixed effects for gender (male, female), age group (<50 years, 50-74 years, 75 years and older), and a random effect for centre.
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.542
    Method
    		 Generalised linear model
    Parameter type
    		 Relative risk
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.07

    Secondary: Time to GI-3 recovery

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    End point title
    		 Time to GI-3 recovery
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
    275
    275
    Attachments
    		 Untitled (Filename: Figure1.jpg)
    Statistical analysis title
    		 Cox-regression model
    Statistical analysis description
    Cox regression adjusted for the minimisation variables; gender, age and centre (the latter via a random effect).
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.849
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.17

    Secondary: Time to return of gut function using the GI-2 recovery

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    End point title
    		 Time to return of gut function using the GI-2 recovery
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
    261
    256
    Attachments
    		 Untitled (Filename: Figure 2.jpg)
    Statistical analysis title
    		 Cox-regression model
    Statistical analysis description
    Cox regression adjusted for the minimisation variables; gender, age and centre (the latter via a random effect).
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.76
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.23

    Secondary: Prolonged Postoperative Ileus

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    End point title
    		 Prolonged Postoperative Ileus
    End point description
    Proportion of patients who failed to establish GI-3 by 120 hours after surgery.
    End point type
    Secondary
    End point timeframe
    120 hours post-operative
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        PPOI
    44
    39
    Statistical analysis title
    		 Generalised linear model
    Statistical analysis description
    Generalised linear model with a logit link function adjusted for the minimisation variables; gender, age and centre (the latter via a random effect).
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.491
    Method
    		 Generalised linear model
    Parameter type
    		 Relative risk
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.61

    Secondary: Daily Postoperative Nausea and Vomiting (PONV) score

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    End point title
    		 Daily Postoperative Nausea and Vomiting (PONV) score
    End point description
    End point type
    Secondary
    End point timeframe
    Daily until 72 hours after start of operation
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        Post-op Day 1: Clinically important - >= 5
    7
    16
        Post-op Day 2: Clinically important - >= 5
    5
    19
        Post-op Day 3: Clinically important - >= 5
    5
    5
    No statistical analyses for this end point

    Secondary: Overall Benefit of Analgesia Score

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    End point title
    		 Overall Benefit of Analgesia Score
    End point description
    Overall Benefit of Analgesia Score
    End point type
    Secondary
    End point timeframe
    Daily in-hospital up to and including postoperative day 7
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    244
    241
    Units: Values
        arithmetic mean (standard deviation)
    2.19 ( 2.55 )
    1.96 ( 2.52 )
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Linear mixed model used to analyse the repeated measures of OBAS outcome adjusted for the minimisation variables; gender, age and centre (the latter via a random effect). Treatment effects at each time were derived from the interaction term for time by treatment.
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.346
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.278
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.856

    Secondary: Total postoperative opioid consumption

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    End point title
    		 Total postoperative opioid consumption
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours post-op
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    210
    210
    Units: OME mg
        median (inter-quartile range (Q1-Q3))
    70.6 (30.0 to 150.0)
    45.0 (17.1 to 98.6)
    No statistical analyses for this end point

    Secondary: Quality of recovery score

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    End point title
    		 Quality of recovery score
    End point description
    Quality of recovery score (15-question patient-reported outcome measure)
    End point type
    Secondary
    End point timeframe
    Daily while in hospital up to 7 days; also days 7 and 30 days after date of operation.
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    238
    240
    Units: Score
        arithmetic mean (standard deviation)
    93.34 ( 9.64 )
    92.91 ( 9.43 )
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Linear mixed model used to analyse the repeated measures of Quality of recovery outcome adjusted for the minimisation variables; gender, age and centre (the latter via a random effect). Treatment effects at each time were derived from the interaction term for time by treatment.
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.801
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.11
         upper limit
    		 2.73

    Secondary: Quality of life assessment - EQ-5D-5L

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    End point title
    		 Quality of life assessment - EQ-5D-5L
    End point description
    End point type
    Secondary
    End point timeframe
    Daily in hospital up to 7 days, day 7, 30 days and 90 days after date of operation.
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    249
    246
    Units: Score
        arithmetic mean (standard deviation)
    0.869 ( 0.149 )
    0.871 ( 0.138 )
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Linear mixed model for repeated measures adjusted for the minimisation variables; gender, age and centre (the latter via a random effect). Treatment effects at each time were derived from the interaction term for time by treatment.
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.917
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.034

    Secondary: Measurement of specific enhanced recovery guideline variables that have been shown to impact GI recovery

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    End point title
    		 Measurement of specific enhanced recovery guideline variables that have been shown to impact GI recovery
    End point description
    Adherence was defined from the following criteria: Postoperative nausea prophylaxis prescribed regularly; No nasogastric tube placed at operation; Total IV fluids in first 24 hrs from start of anaesthesia <4litres (any fluid type); Preoperative carbohydrate loading drink given; Day 1 mobilisation target achieved; Food offered day 1; Supplement drinks given on day of surgery; IV fluids discontinued within 48 hours of start of operation; Urinary catheter removed within 48 hours of start of operation; Mobilisation target achieved (out of bed for at least 4 hours day 2). “High” adherence was defined if a patient met 7 or more criteria and “low” adherence defined if a patient met less than 5 criteria.
    End point type
    Secondary
    End point timeframe
    End of inpatient admission
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        High
    100
    91
        Moderate
    131
    143
        Low
    48
    44
    No statistical analyses for this end point

    Secondary: Time to achievement of medical criteria for discharge

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    End point title
    		 Time to achievement of medical criteria for discharge
    End point description
    Time (days) to meeting medically-defined hospital discharge criteria (independent hydration/nutrition, adequate analgesia by oral route, independent mobilisation, return of gut function by GI-3 definition, no medical contraindication)
    End point type
    Secondary
    End point timeframe
    End of inpatient admission
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        Achieved medical criteria
    278
    277
    Statistical analysis title
    		 Cox-regression model
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.914
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.17

    Secondary: Patient-reported assessment of readiness for discharge

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    End point title
    		 Patient-reported assessment of readiness for discharge
    End point description
    Time (days) to patient-reported readiness for discharge (must also have achieved medical criteria for discharge as noted above)
    End point type
    Secondary
    End point timeframe
    Assessed daily from day 2 onward
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        Patient fit for discharge
    278
    277
    Statistical analysis title
    		 Cox regression model
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.867
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.17

    Other pre-specified: Total length of hospital stay

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    End point title
    		 Total length of hospital stay
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Total duration of primary admission and any readmission within 30 days
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    277
    Units: days
        arithmetic mean (standard deviation)
    6.0 ( 5.9 )
    5.8 ( 4.5 )
    Statistical analysis title
    		 Incidence rate ratio
    Comparison groups
    IV Lidocaine v Placebo
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.648
    Method
    		 Poisson
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.14

    Other pre-specified: 30-days mortality

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    End point title
    		 30-days mortality
    End point description
    End point type
    Other pre-specified
    End point timeframe
    30 days after date of operation.
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        Died
    1
    2
    No statistical analyses for this end point

    Other pre-specified: 90 days mortality

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    End point title
    		 90 days mortality
    End point description
    End point type
    Other pre-specified
    End point timeframe
    90 days after date of operation
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        Died
    2
    3
    No statistical analyses for this end point

    Other pre-specified: Unplanned re-admissions within 90 days of date of operation

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    End point title
    		 Unplanned re-admissions within 90 days of date of operation
    End point description
    End point type
    Other pre-specified
    End point timeframe
    90 days from date of operation
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    277
    Units: Total
        No with unplanned re-admission
    31
    34
    No statistical analyses for this end point

    Other pre-specified: Unplanned re-admission after discharge, and within 30 days of operation

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    End point title
    		 Unplanned re-admission after discharge, and within 30 days of operation
    End point description
    End point type
    Other pre-specified
    End point timeframe
    30 days from date of operation
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    277
    Units: Total
        No with unplanned re-admission
    10
    23
    No statistical analyses for this end point

    Other pre-specified: Major complications

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    End point title
    		 Major complications
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Up to 30 days from date of operation
    End point values
    		 IV Lidocaine Placebo
    Number of subjects analysed
    279
    278
    Units: Total
        Complication of Clavien-Dindo grade 3 and above
    13
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days post-operation
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    IV Lidocaine
    Reporting group description
    		 Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride

    Reporting group title
    Placebo
    Reporting group description
    		 0.9% sterile Sodium Chloride solution for injection.

    Serious adverse events
    		 IV Lidocaine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 279 (1.43%)
    9 / 278 (3.24%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Procedural haemorrhage, Anastomotic haemorrhage, Gastrointestinal procedural complication,
    Additional description: Other term: Postoperative wound complication
         subjects affected / exposed
    2 / 279 (0.72%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia, Atrial fibrillation
         subjects affected / exposed
    0 / 279 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 279 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 278 (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
    Postoperative wound infection
         subjects affected / exposed
    0 / 279 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 IV Lidocaine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 279 (12.90%)
    27 / 278 (9.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm recurrence
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 278 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Anastomotic leak, Gastrointestinal procedural complication, Postoperative ileus
    Additional description: Stoma complications, Toxicity to various agents, Postoperative wound complication, Post procedural haemorrhage
         subjects affected / exposed
    24 / 279 (8.60%)
    19 / 278 (6.83%)
         occurrences all number
    43
    25
    Cardiac disorders
    Bradycardia, Supraventricular tachycardia, Nodal arrhythmia, Atrial fibrillation, Sinus arrhythmia,
    Additional description: Tachycardia
         subjects affected / exposed
    10 / 279 (3.58%)
    4 / 278 (1.44%)
         occurrences all number
    10
    4
    Nervous system disorders
    Headache, Cerebrovascular accident, Aphasia, Dizziness
         subjects affected / exposed
    1 / 279 (0.36%)
    3 / 278 (1.08%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Oedema peripheral, Hyperhidrosis, Adverse drug reaction, Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 279 (0.72%)
    2 / 278 (0.72%)
         occurrences all number
    2
    3
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 278 (0.36%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Melaena, Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 279 (0.36%)
    1 / 278 (0.36%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Pruritus, Decubitus ulcer
         subjects affected / exposed
    0 / 279 (0.00%)
    2 / 278 (0.72%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Psychotic disorder, Confusional state
         subjects affected / exposed
    1 / 279 (0.36%)
    3 / 278 (1.08%)
         occurrences all number
    1
    3
    Renal and urinary disorders
    Urinary retention, Acute kidney injury
         subjects affected / exposed
    2 / 279 (0.72%)
    1 / 278 (0.36%)
         occurrences all number
    2
    1
    Infections and infestations
    Pelvic abscess, Lower respiratory tract infection, Postoperative wound infection, COVID-19
    Additional description: Abdominal infection, Pneumonia, Influenza, Herpes zoster, Urinary tract infection, Stoma site infection
         subjects affected / exposed
    9 / 279 (3.23%)
    8 / 278 (2.88%)
         occurrences all number
    9
    9
    Metabolism and nutrition disorders
    Hypokalaemia, Hypophosphataemia
         subjects affected / exposed
    1 / 279 (0.36%)
    1 / 278 (0.36%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2019
    Administrative changes. Clarification of definition of reoperation/major complications. Addition of benign polyps and benign stricture to the inclusion criteria. Change of processes around co-enrolment, recording participants who do not complete questionnaires. Clarification of prohibited medications and adverse event recording (including common events after surgery). Addition of new section on data management (personal data, transfer of data, data controller, data breaches).
    08 Sep 2020
    Administrative changes. Removal of exploratory open RCT. Clarification on the use of robotic laparoscopic surgery. Changes to consent procedures, including consent by phone and post to give greater flexibility during COVID.
    17 Mar 2022
    Administrative changes. Change to the study duration - following an extension to the recruitment period. Clarification to protocol text - including updates to remove text relating to primary endpoint that is not applicable due to the time frame around the endpoint of 72 hours. Clarification on the recording of post randomisation exclusions. Clarification to emergency unblinding text to add in information about conversions from minimally invasive to open surgeries.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    Recruitment to ALLEGRO was paused on 20 March 2020 at the start of the COVID-19 pandemic. The Sponsor agreed to re-open recruitment on 7 July 2020. The essential nature of this type of surgery (predominantly for cancer) meant that eligible cases were presenting during the pandemic. The original design of the study had integrated trial processes into existing surgical patient pathways, therefore no change of trial design was required to mitigate the impact of COVID. However, as noted above, an amendment was approved to permit verbal agreement prior to written informed consent to permit randomisation in advance of admission.
    07 Jul 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    For pragmatic reasons relatively short durations of infusion were delivered in ALLEGRO - we cannot discount the possibility that longer duration might be effective.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/39602290
    http://www.ncbi.nlm.nih.gov/pubmed/35090535
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