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Trial registered on ANZCTR


Registration number
ACTRN12619001521112p
Ethics application status
Not yet submitted
Date submitted
22/10/2019
Date registered
4/11/2019
Date last updated
4/11/2019
Date data sharing statement initially provided
4/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Lignocaine versus opioids in myocardial infarction (AVOID-2)
Scientific title
Lignocaine versus opioids as analgesia in myocardial infarction - assessment of efficacy and safety
Secondary ID [1] 299610 0
None
Universal Trial Number (UTN)
nil
Trial acronym
AVOID-2
Linked study record
n/a

Health condition
Health condition(s) or problem(s) studied:
Acute myocardial infarction 314900 0
ST elevation myocardial infarction 314901 0
Condition category
Condition code
Cardiovascular 313257 313257 0 0
Coronary heart disease
Anaesthesiology 313334 313334 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomised to receive lignocaine as analgesia in STEMI at a dose of 50mg intravenously over 2 minutes if weight is less than 70kg or 100mg intravenously over 2 minutes if weight is equal to or over 70kg. An additional 50-100mg may be administered every 15 minutes (maximum 300mg total dose) thereafter if patients have a pain score of greater than or equal to 5 (NRS) .
Intervention code [1] 315864 0
Treatment: Drugs
Comparator / control treatment
The comparator arm will be the current Ambulance Victoria clinical practice guideline for analgesia in myocardial infarction which is intravenous fentanyl up to 50mcg every 5 minutes provided pain score is greater than or equal to 5 (NRS) until handover of care to Emergency department
Control group
Active

Outcomes
Primary outcome [1] 321750 0
Pre-hospital change in pain score based on a verbal numerical reporting scale (NRS)
Timepoint [1] 321750 0
Change in pain from maximal pain score (NRS) recorded by Ambulance Victoria on patient attendance to pain score on hospital arrival.
Primary outcome [2] 321751 0
Primary composite safety endpoint: Bradyarrhythmia or seizures requiring pharmacological intervention, respiratory depression requiring pharmacological intervention (e.g. naloxone)
Bradyarrhythmia defined as heart rate less than 60 with symptomatic or haemodynamic compromise prompting administration of chronotropic agent (assessed by 12-lead ECG and clinical assessment - recorded on study specific questionnaire)
Seizures - defined as observed generalised tonic-clonic activity prompting administration of anticonvulsant - assessed by clinical assessment - recorded on study specific questionnaire
Respiratory depression defined as respiratory rate less than 12 with hypoxaemia and GCS less than 15 prompting administration of naloxone (determined by clinical assessment and recorded on study specific questionnaire)
Timepoint [2] 321751 0
During prehospital transport of patient to emergency department by Ambulance Victoria
Secondary outcome [1] 376111 0
1. Proportion of patients reporting no to mild pain (NRS 0-4) on arrival to hospital.
Timepoint [1] 376111 0
Hospital arrival
Secondary outcome [2] 376112 0
2. Proportion of patients with moderate to severe pain (NRS score of 5 or higher) at hospital arrival in both groups
Timepoint [2] 376112 0
Hospital arrival
Secondary outcome [3] 376113 0
Proportion of patients requiring rescue opioids in Lignocaine group defined as proportion of patients with pain score of 5 or greater despite lignocaine administration that are then given opioid analgesia.
Timepoint [3] 376113 0
Prehospital transfer
Secondary outcome [4] 376114 0
Mean pain score on arrival to hospital in both groups defined as average verbally reported pain score (numerical rating scale) prior to handover of patient to Emergency Department staff
Timepoint [4] 376114 0
Hospital arrival
Secondary outcome [5] 376115 0
Ambulance paramedic observed ventricular fibrillation or ventricular tachycardia requiring DC reversion or amiodarone infusion during transfer to emergency department
Timepoint [5] 376115 0
During prehospital transport of patient to emergency department
Secondary outcome [6] 376116 0
adverse events related to lignocaine administration determined by clinical assessment performed by paramedics defined as presence of;
complete heart block or ventricular pauses greater than 3 seconds
Tongue paraesthesia
Respiratory rate less than 12 breaths per minute with oxygen saturations less than 90%
Decreased GCS greater than two points from baseline
generalised tonic-clonic seizure activity
Patient reported tinnitus or diplopia
Urticarial rash

Adverse reaction related to fentanyl administration determined by clinical assessment performed by paramedics:
Respiratory depression defined as respiratory rate less than 12 breaths per minute with oxygen saturations less than 90%
nausea and/or vomiting requiring anti-emetic treatment
Decrease in GCS greater than two points from baseline

Findings will be reported on study specific questionnaires
Timepoint [6] 376116 0
During prehospital transport of patient to emergency department
Secondary outcome [7] 376117 0
In the subgroup of patients with confirmed STEMI on angiography: Infarct size at hospital discharge based on peak cardiac troponin I
Timepoint [7] 376117 0
plasma cardiac troponin I (cTnI) on admission and 6 hourly for the first 48 hours and 12 hourly between 48-72 hours
Secondary outcome [8] 376119 0
Survival to hospital discharge
Timepoint [8] 376119 0
Assessed at hospital discharge
Secondary outcome [9] 376120 0
pre-percutaneous coronary intervention Thrombolysis in Myocardial Infarction (TIMI) flow rate as determined angiographically as follows:
TIMI-0 - No perfusion. There is no antegrade flow beyond the obstruction in an occluded artery.
• TIMI-1 - Partial, but incomplete filling of the coronary artery. Contrast material passes beyond the area of obstruction but fails to opacify the entire coronary bed distal to the obstruction for the duration of the angiographic panning.
• TIMI-2 - Partial perfusion. Contrast material passes across the obstruction and opacifies the coronary artery distal to the obstruction. However, the rate of entry of contrast material into the vessel distal to the obstruction or its rate of clearance from the distal bed, or both, is perceptibly slower than the flow into or rate of clearance from comparable areas not perfused by the previously occluded or infarct-related vessel (e.g., opposite coronary artery or the coronary bed proximal to the obstruction).
• TIMI-3 - Complete and brisk flow/complete perfusion. Ante-grade flow into the bed distal to the obstruction, and clearance of contrast material from the involved bed as rapid as clearance from an uninvolved bed in the same vessel or the opposite artery.
Timepoint [9] 376120 0
At time of percutaneous coronary intervention which will be wihtin 24 hours of hospital admission
Secondary outcome [10] 376121 0
Proportion of patients with a change in ST-segment elevation by greater than 50% on arrival to hospital as assess by 12-lead ECG by ambulance paramedics
Timepoint [10] 376121 0
on arrival of patient to hospital
Secondary outcome [11] 376122 0
Major adverse cardiac events which is a composite of
All cause death
Myocardial infarction defined as Troponin T or I greater than the diagnostic cut-off for the assay on at least one occasion during admission or total CK greater than two times the upper limit of normal with either ischaemic ECG changes or ischaemic chest pain or chest pain equivalent as documented in hospital notes
Stroke - Persistent loss of neurological function caused by an ischaemic or haemorrhagic event as documented in hospital notes
Repeat unplanned percutaneous coronary intervention as documented in hospital notes
Unplanned coronary artery bypass graft surgery as documented in hospital notes
Unplanned hospital admission for heart failure as documented in hospital notes

, re-hospitalisation at 6 months
Timepoint [11] 376122 0
6 months post index event
Secondary outcome [12] 376294 0
In the subgroup of patients with confirmed STEMI on angiography:
measure of infarct size based on cardiac troponin I area under the curve in first 72 hours in each group measured using serum assay
Timepoint [12] 376294 0
Area under the curve based on cardiac troponin measurement on arrival to hospital, 6 hourly for first 48 hours then 12 hourly for further 24 hours
Secondary outcome [13] 376295 0
In the subgroup of patients with confirmed STEMI on angiography:
Infarct size as measured by peak creatine kinase (CK) in each group measured using serum assay
Timepoint [13] 376295 0
Creatine kinase measured at hospital admission and then 6 hourly in first 48 hours then 12 hourly for further 24 hours
Secondary outcome [14] 376296 0
In the subgroup of patients with confirmed STEMI on angiography:
infarct size in each group as measured by creatine kinase (CK) area under the curve in each group measured using serum assay
Timepoint [14] 376296 0
Creatine kinase at baseline and 6 hourly in the first 48 hours then 12 hourly for the next 24 hours

Eligibility
Key inclusion criteria
• Adult age greater than or equal to 18 years or older
• 12-lead ECG consistent with STEMI
• Chest pain greater than or equal to 5/10
• Transfer to a primary PCI centre in metropolitan Melbourne
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• No IV inserted
• Opioids administered prior to randomisation
• Known hypersensitivity to opioids or lignocaine
• HR < 50 bpm
• Out of hospital cardiac arrest (chest compressions or defibrillation) or cardiogenic shock (SBP<90mmHg)
• Regular opioid use
• Past history of epilepsy
• Stage IV or V chronic kidney disease
• Known cirrhotic liver disease
• Patient dependent on others for activities of daily living

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment will be performed as follows:
Ambulance Victoria ALS and MICA paramedics will be provided with randomisation envelopes. Half in each pack will contain instructions for administering intravenous lignocaine and half will contain instructions for administering fentanyl as per study protocol. The envelopes will be randomised by computer-generated code into blocks of ten, numbered externally, and then sealed within an opaque envelope that conceals the treatment designation. All vehicles will carry three envelopes and as each is used, it will be replaced at the earliest convenient time from the remaining envelopes held at the ambulance station.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Envelopes will be randomised by computer-generated code into blocks of ten as previously undertaken by Ambulance Victoria
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
All patients allocated to each group will be considered as comprising the intention-to treat population for all primary and secondary analyses. Infarct size will be assessed by cardiac biomarkers. Data analyses will be performed using the statistical package SPSS version 23 (IBM Corporation, Armonk, NY, USA). Variables that approximate a normal distribution will be summarised as mean ± standard deviation, and groups compared using T-Tests. Non-normal variables will be summarised as median and first and third quartiles (Q1, Q3), and groups compared using Mann-Whitney Rank sum tests with exact inference. Binomial variables will be expressed as proportions and 95% confidence intervals (exact binomial) and groups compared by Chi-Squared tests.

Between group comparisons of area under the curves for cTnI and CK release, the time of ischaemia, the area at risk and the infarct size as assessed by MRI will be performed using the Wilcoxon rank-sum test. A comparison of the incidence of cumulative adverse clinical events between the two groups will be performed by means of Fisher’s exact test.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 304087 0
Charities/Societies/Foundations
Name [1] 304087 0
National Heart Foundation Vanguard grant
Address [1] 304087 0
2/850 Collins St,
Melbourne
VIC 3008
Country [1] 304087 0
Australia
Primary sponsor type
Government body
Name
Ambulance Victoria
Address
31 Joseph Street Blackburn North
Victoria
3130
Country
Australia
Secondary sponsor category [1] 304294 0
None
Name [1] 304294 0
N/A
Address [1] 304294 0
N/A
Country [1] 304294 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 304576 0
Alfred HREC
Ethics committee address [1] 304576 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 304576 0
Australia
Date submitted for ethics approval [1] 304576 0
08/11/2019
Approval date [1] 304576 0
Ethics approval number [1] 304576 0

Summary
Brief summary
There is some concern that medications called opioids, which are used to treat pain, may delay the onset of blood thinning medications that are vital to improving patient outcomes after a heart attack. This study seeks to enrol patients suspected of having a heart attack to compare the safety and effectiveness of a different type of painkiller called lignocaine (which does not appear to interact with blood thinners) to fentanyl which is the current standard of care opioid used. We hypothesise that use of lignocaine will be safe and effective for pain related to a heart attack. Ambulance Victoria paramedics will randomise patients with suspected heart attacks to receive either intravenous lignocaine or intravenous fentanyl and assess its effectiveness as pain relief and also side effects (safety) in each group. We will also assess size of the heart attack based on blood testing as well as clinical outcomes during follow-up.
Trial website
NA
Trial related presentations / publications
NA
Public notes

Contacts
Principal investigator
Name 97446 0
A/Prof Dion Stub
Address 97446 0
Heart Centre, Level 3
55 Commercial Rd
Melbourne
Victoria
3004
Country 97446 0
Australia
Phone 97446 0
+61 390762000
Fax 97446 0
Email 97446 0
d.stub@alfred.org.au
Contact person for public queries
Name 97447 0
A/Prof Dion Stub
Address 97447 0
Heart Centre, Level 3
55 Commercial Rd
Melbourne
Victoria
3004
Country 97447 0
Australia
Phone 97447 0
+61 390762000
Fax 97447 0
Email 97447 0
d.stub@alfred.org.au
Contact person for scientific queries
Name 97448 0
Dr Himawan Fernando
Address 97448 0
Heart Centre, Level 3
Alfred Hospital
55 Commercial Rd
Melbourne
VIC
3004
Country 97448 0
Australia
Phone 97448 0
+61 390762000
Fax 97448 0
Email 97448 0
h.fernando@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will be aggregated in the analysis and de-identified. As such invididual participant data will not be available.
What supporting documents are/will be available?
No other documents available
Summary results
No Results