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Trial registered on ANZCTR


Registration number
ACTRN12621001549819
Ethics application status
Approved
Date submitted
20/09/2021
Date registered
15/11/2021
Date last updated
20/09/2022
Date data sharing statement initially provided
15/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Pharmacokinetics of Perioperative Lignocaine
Scientific title
Continuous Lignocaine Infusion Pharmacokinetics in the Perioperative Period (CLIPP)
Secondary ID [1] 305357 0
Nil Known
Universal Trial Number (UTN)
U1111-1269-5693
Trial acronym
CLIPP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peri-operative Pain 323690 0
Condition category
Condition code
Anaesthesiology 321223 321223 0 0
Pain management

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The following describes the use of lignocaine for all patients at the study site, regardless of whether they participate in this study. Lignocaine infusions will be initiated in the operating theatre at induction of anaesthesia. The attending anaesthetist will be responsible for preparation of lignocaine for infusion according to their institutional protocol.

All patient's included in the study would be planned to receive a lignocaine bolus and infusion as part of their anaesthetic and/or post-operative care regardless of their involvement in the study.

An intravenous bolus (loading) dose and continuous infusion will be administered using the following protocol:

Bolus Dose:
Following anaesthesia induction, a bolus of intravenous lignocaine will be delivered slowly over the course of 2-3 minutes
Dosed at 1.5mg/kg to a maximum of 150mg
Dosing will be based on ideal body weight (IBW) according to the Devine formula.

Continuous Infusion:
After the bolus dose has been delivered a lignocaine infusion at 1.5mg/kg/hr (to a maximum of 150mg/hr) will be commenced via an infusion pump.

Dosing will be based on ideal body weight according to the Devine formula.

The duration of the infusion and decision of when to cease will be at the discretion of the attending anaesthetist or pain physician (if the patient has been admitted to the ward).
IV lignocaine infusions will be administered up to 48 hours.

Ward management of the IV lignocaine infusion will be according to institutional lignocaine infusion protocols. If toxicity develops the patient will be reviewed by the Pain Service or On-call anaesthetist and lignocaine infusion stopped or titrated down as per the institutional lignocaine infusion policy.

The Devine Formula for Ideal Body Weight:
Male ideal body weight(kg) = 50 + (0.91 * (Height in cm -152.4))
Female Ideal body weight (kg) = 45.5 + (0.91 * (Height in cm -152.4))

Intraoperative and Postoperative phase:

- Peripheral blood collection for the quantification of lignocaine concentration (free and bound), metabolite concentration and Alpha 1 acid glycoprotein levels
- Documentation of any adverse symptoms associated with the use of lignocaine from the induction of anaesthesia until 4 hours after the lignocaine infusion is ceased. This will be done as brief questioning in recovery and every 24 hours (out to 48 hours following infusion start) take roughly 5 mins for each session. This is done as part of standard care on lignocaine infusion currently so does not represent a deviation from normal care.

A total of 8 lignocaine levels will be done during the study period. 3 levels will be done intra-operatively, shortly prior to and after starting the infusion. The remaining 5 will be completed over the remaining 48 hours (with 3 levels shortly after cessation of the infusion). Each blood test is anticipated to take roughly 5-10 minutes.
Intervention code [1] 321762 0
Not applicable
Comparator / control treatment
No Control
Control group
Uncontrolled

Outcomes
Primary outcome [1] 329012 0
A pharmacokinetic model, parameterised in terms of clearances and volumes, describing total and unbound lignocaine concentrations as determined using venous whole blood samples
Timepoint [1] 329012 0
A total of 8 lignocaine levels will be done during the study period. 3 levels will be done intra-operatively, shortly prior to and after starting the infusion. The remaining 5 will be completed over the remaining 48 hours (with 3 levels shortly after cessation of the infusion). Optimal design will be used to identify the best time to take samples given a particular study design to maximise the information obtained about model parameters. To identify optimal sample windows, we will use PopED version 0.6.0 in R v 4.0.3 with R Studio (RStudio Team (2016). Timing of sampling will be continually reviewed during the study period to optimise information obtained.
Primary outcome [2] 329424 0
: A pharmacokinetic model, parameterised in terms of clearances and volumes, describing total and unbound concentrations of lignocaine's primary metabolite monoethylglycinexylidide (MEGX), determined using venous whole blood samples
Timepoint [2] 329424 0
A total of 8 monoethylglycinexylidide (MEGX) levels will be done during the study period. 3 levels will be done intra-operatively, shortly prior to and after starting the infusion. The remaining 5 will be completed over the remaining 48 hours (with 3 levels shortly after cessation of the infusion). Optimal design will be used to identify the best time to take samples given a particular study design to maximise the information obtained about model parameters. To identify optimal sample windows, we will use PopED version 0.6.0 in R v 4.0.3 with R Studio (RStudio Team (2016). Timing of sampling will be continually reviewed during the study period to optimise information obtained.
Secondary outcome [1] 401158 0
Alpha-1 glycoprotein levels pre and post operatively using population pharmacokinetic models using venous whole blood samples
Timepoint [1] 401158 0
The preoperative concentration will be measured at the same time as standard preoperative clinical bloodwork. The postoperative concentration will be taken within 48 h of surgery and at a time that other blood work is being taken to minimise the impact on patients.
Secondary outcome [2] 401159 0
Signs and symptoms of local anaesthetic systemic toxicity assessed using physical examination and documented in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0)'
Timepoint [2] 401159 0
This will be done as brief questioning in recovery and every 24 hours (out to 48 hours following infusion start), taking roughly 5 mins for each session. This is done as part of standard care on lignocaine infusion currently so does not represent a deviation from normal care.

Eligibility
Key inclusion criteria
- Age 18 years or older
- Patients must be able to give informed consent
- Patients undergoing surgery in whom the attending anaesthetist plans to use intravenous lignocaine per local protocol for the duration of the procedure or longer
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Decline to participate
- Unable to consent due to language barrier or cognitive decline
- Allergy to amide type local anaesthetic solutions
- ASA 4/5/6
- Cardiac conduction defect 2nd or 3rd degree heart block or sinoatrial block without pacemaker
- Bradycardia or pre-existing hypotension
- Haemodynamic instability or hypovolaemia
- Uncontrolled epilepsy
- Patients taking other class 1 anti-arrhythmic agents or amiodarone
- Planned local anaesthetic infusions through neuraxial (e.g. epidural) or regional (wound catheters) routes of administration.
- Pregnancy and Breastfeeding
- Lignocaine infusion total duration (including bolus) of under 2 hours

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Optimal design will be used to identify the best time to take samples given a particular study design in order to maximise the information obtained about model parameters. This enables us to minimise sampling on individuals by planning our pharmacokinetic study better. To identify optimal sample windows, we will use PopED version 0.6.0 in R v 4.0.3 with R Studio (RStudio Team (2016). RStudio: Integrated Development for R. RStudio, Inc., Boston, MA URL http://www.rstudio.com/). The windows will be those that maximise the expected precision of parameter estimates for a 3-compartment model of lignocaine. We will conduct our optimal design by randomly sampling a set of covariate distributions from a large database of thousands of real patient profiles (age, sex, weight and height) to ensure our design is based on a realistic population. We will limit our study design to 50 participants and a maximum of 8 samples each. Fifty patients should provide sufficient modelling power based on previous work in this field.

We will model both lignocaine and MEGX kinetics using compartment models. Clearance of lignocaine to MEGX will be assumed to be irreversible. As the volume of the metabolite compartment will be unidentifiable (without an IV input of metabolite) we will fix this to the volume of lignocaine to avoid underestimating metabolite formation. We will explore models of pharmacokinetic interactions to see if we can elucidate a mechanism for reported changes in lignocaine clearance over extended infusion durations as a result of MEGX. We will also explore models of protein binding to characterise the unbound and total drug concentration time course. Once a structural pharmacokinetic model has been developed, we will consider incorporation of key covariates to better describe variability in observed concentrations following standard dosing in our population.

Analyses will be using standard methodology for nonlinear mixed effects models (NONMEM 7.5, Globomax LLC, Hanover, MD, USA). Convergence criterion will be to three significant digits. Model selection will require a statistically significant improvement in the NONMEM objective function between nested models (p<0.05), equating to a reduction >3.84 based on a chi-square distribution with one degree of freedom, and inspection of standard goodness of fit plots. Non-parametric bootstrap methods, with 1000 simulations, will be used to estimate confidence intervals as a measure of parameter uncertainty. Visual predicted checks (VPC) will be used to visualise prediction intervals superimposed on observed data to evaluate how well the model predicted the distribution of observations (using 1000 simulation replicates). We will a priori assume allometric scaling of clearances and volumes to body size with theoretical exponents. Simulation methods will be used to explore current dosing regimens using the final model.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/12/2021
Actual
17/02/2022
Date of last participant enrolment
Anticipated
29/12/2023
Actual
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
50
Accrual to date
12
Final
Recruitment outside Australia
Country [1] 24139 0
New Zealand
State/province [1] 24139 0
Auckland

Funding & Sponsors
Funding source category [1] 309727 0
Charities/Societies/Foundations
Name [1] 309727 0
The Auckland Medical Research Foundation
Country [1] 309727 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
85 Park Road
Grafton
Auckland 1023
New Zealand
Country
New Zealand
Secondary sponsor category [1] 310746 0
None
Name [1] 310746 0
Address [1] 310746 0
Country [1] 310746 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309486 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 309486 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 309486 0
New Zealand
Date submitted for ethics approval [1] 309486 0
21/10/2021
Approval date [1] 309486 0
18/11/2021
Ethics approval number [1] 309486 0
2021 EXP 11189

Summary
Brief summary
Significance:
The use of intravenous lignocaine infusions during the perioperative period as analgesic adjuncts is increasingly popular. However, dosing is empirical and standardised across pain settings without consideration of patient and surgical factors which may influence pharmacokinetics and therefore analgesia. Current dosing has resulted in plasma concentrations of total lignocaine that exceed the widely accepted toxic plasma concentration of 5 µg/ml. The kinetics of the parent and metabolite over longer durations is unknown. A robust pharmacokinetic model for lignocaine and its metabolite will provide a means to rationally adjust dose for different pain settings, populations, and over longer treatment durations without compromising patient safety.

Context:
This is an observational multicentre study at Waitemata District Health Board, Auckland District Health Board and Counties Manukau District Health Board. It will involve specialist researchers from North Shore Hospital, Auckland City Hospital, and Middlemore Hospital (Pain Medicine, Anaesthesiology and Perioperative Medicine), and The University of Auckland (Anaesthesiology and Pharmacology).

Aims and Objectives:
The objective of this work is to contribute to the safe and effective use of lignocaine in the perioperative period by developing a robust pharmacokinetic model that can be used to rationally select dosing regimens to achieve and maintain safe target concentrations while avoiding those associated with toxicity.
The study aims to characterise the pharmacokinetic profile of lignocaine and its primary metabolite monoethylglycinexylidide (MEGX) using population pharmacokinetic models.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114314 0
Dr Daniel Chiang
Address 114314 0
Department of Anaesthesiology and Perioperative Medicine, WDHB, North Shore Hospital, Private Bag 93503,
Takapuna, North Shore City 0740
Country 114314 0
New Zealand
Phone 114314 0
+64 94861491
Fax 114314 0
+6494868993
Email 114314 0
[email protected]
Contact person for public queries
Name 114315 0
Daniel Chiang
Address 114315 0
Department of Anaesthesiology and Perioperative Medicine, WDHB, North Shore Hospital, Private Bag 93503,
Takapuna, North Shore City 0740
Country 114315 0
New Zealand
Phone 114315 0
+64 94861491
Fax 114315 0
+6494868993
Email 114315 0
[email protected]
Contact person for scientific queries
Name 114316 0
Daniel Chiang
Address 114316 0
Department of Anaesthesiology and Perioperative Medicine, WDHB, North Shore Hospital, Private Bag 93503,
Takapuna, North Shore City 0740
Country 114316 0
New Zealand
Phone 114316 0
+64 94861491
Fax 114316 0
+6494868993
Email 114316 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.