Clinical Trial Results:
A placebo controlled randomised trial of intravenous lidocaine in accelerating gastrointestinal recovery after colorectal surgery
Summary
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EudraCT number |
2017-003835-12 |
Trial protocol |
GB |
Global end of trial date |
10 Aug 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Feb 2025
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First version publication date |
02 Feb 2025
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AC17067
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University of Edinburgh & NHS Lothian
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Sponsor organisation address |
47 Little France Crescent, Edinburgh , United Kingdom, EH16 4TJ
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Public contact |
Seonaidh Cotton, The University of Aberdeen, s.c.cotton@abdn.ac.uk
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Scientific contact |
Thenmalar Vadiveloo, The University of Aberdeen, thenmalar.vadiveloo@abdn.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Dec 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Apr 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Aug 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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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).
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Protection of trial subjects |
None
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 557
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Worldwide total number of subjects |
557
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
238
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From 65 to 84 years |
303
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85 years and over |
16
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Recruitment
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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
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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
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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IV Lidocaine | |||||||||
Arm description |
Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
IV Lidocaine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Infusion
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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.
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Arm title
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Placebo | |||||||||
Arm description |
0.9% sterile Sodium Chloride solution for injection. | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
IV Lidocaine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Infusion
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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.
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Infusion same as IV lidoacaine arm
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Baseline characteristics reporting groups
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Reporting group title |
IV Lidocaine
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Reporting group description |
Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
0.9% sterile Sodium Chloride solution for injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
IV Lidocaine
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Reporting group description |
Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride | ||
Reporting group title |
Placebo
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Reporting group description |
0.9% sterile Sodium Chloride solution for injection. |
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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).
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End point type |
Primary
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End point timeframe |
72 hours post-operative
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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.
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Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
557
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.542 | |||||||||||||||
Method |
Generalised linear model | |||||||||||||||
Parameter type |
Relative risk | |||||||||||||||
Point estimate |
0.97
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.88 | |||||||||||||||
upper limit |
1.07 |
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End point title |
Time to GI-3 recovery | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
90 days
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Attachments |
Untitled (Filename: Figure1.jpg) |
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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).
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Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
557
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.849 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.98
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.83 | |||||||||
upper limit |
1.17 |
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End point title |
Time to return of gut function using the GI-2 recovery | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
90 days
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Attachments |
Untitled (Filename: Figure 2.jpg) |
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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).
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Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
557
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.76 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
1.03
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.86 | |||||||||
upper limit |
1.23 |
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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.
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End point type |
Secondary
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End point timeframe |
120 hours post-operative
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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).
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Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
557
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.491 | ||||||||||||
Method |
Generalised linear model | ||||||||||||
Parameter type |
Relative risk | ||||||||||||
Point estimate |
1.13
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.8 | ||||||||||||
upper limit |
1.61 |
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End point title |
Daily Postoperative Nausea and Vomiting (PONV) score | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Daily until 72 hours after start of operation
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No statistical analyses for this end point |
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End point title |
Overall Benefit of Analgesia Score | ||||||||||||
End point description |
Overall Benefit of Analgesia Score
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End point type |
Secondary
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End point timeframe |
Daily in-hospital up to and including postoperative day 7
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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.
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Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
485
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.346 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.278
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.3 | ||||||||||||
upper limit |
0.856 |
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End point title |
Total postoperative opioid consumption | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 24 hours post-op
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No statistical analyses for this end point |
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End point title |
Quality of recovery score | ||||||||||||
End point description |
Quality of recovery score (15-question patient-reported outcome measure)
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End point type |
Secondary
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End point timeframe |
Daily while in hospital up to 7 days; also days 7 and 30 days after date of operation.
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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.
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Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
478
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.801 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.31
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-2.11 | ||||||||||||
upper limit |
2.73 |
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End point title |
Quality of life assessment - EQ-5D-5L | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Daily in hospital up to 7 days, day 7, 30 days and 90 days after date of operation.
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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.
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Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
495
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.917 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.002
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.038 | ||||||||||||
upper limit |
0.034 |
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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.
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End point type |
Secondary
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End point timeframe |
End of inpatient admission
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No statistical analyses for this end point |
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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)
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End point type |
Secondary
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End point timeframe |
End of inpatient admission
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Statistical analysis title |
Cox-regression model | ||||||||||||
Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
557
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.914 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.99
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Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.84 | ||||||||||||
upper limit |
1.17 |
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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)
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End point type |
Secondary
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End point timeframe |
Assessed daily from day 2 onward
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Statistical analysis title |
Cox regression model | ||||||||||||
Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
557
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.867 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.99
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Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.83 | ||||||||||||
upper limit |
1.17 |
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End point title |
Total length of hospital stay | ||||||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
Total duration of primary admission and any readmission within 30 days
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Statistical analysis title |
Incidence rate ratio | ||||||||||||
Comparison groups |
IV Lidocaine v Placebo
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Number of subjects included in analysis |
556
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.648 | ||||||||||||
Method |
Poisson | ||||||||||||
Parameter type |
Incidence rate ratio | ||||||||||||
Point estimate |
1.03
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Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.92 | ||||||||||||
upper limit |
1.14 |
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End point title |
30-days mortality | ||||||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
30 days after date of operation.
|
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|
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No statistical analyses for this end point |
|
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End point title |
90 days mortality | ||||||||||||
End point description |
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End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
90 days after date of operation
|
||||||||||||
|
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No statistical analyses for this end point |
|
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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
|
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|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Unplanned re-admission after discharge, and within 30 days of operation | ||||||||||||
End point description |
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End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
30 days from date of operation
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
Up to 30 days post-operation
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
|
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Reporting groups
|
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Reporting group title |
IV Lidocaine
|
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Reporting group description |
Sterile solution of Lidocaine 2% made isotonic with Sodium Chloride | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
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Reporting group description |
0.9% sterile Sodium Chloride solution for injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||
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 | |||||||
|
|||||||
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 |