Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000264583
Ethics application status
Approved
Date submitted
22/01/2015
Date registered
20/03/2015
Date last updated
18/03/2019
Date data sharing statement initially provided
18/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised controlled trial investigating the effects of early snake antivenom administration
Scientific title
Randomised controlled trial investigating the effects of early snake antivenom administration
Secondary ID [1] 286041 0
Nil
Universal Trial Number (UTN)
U1111-1166-4694
Trial acronym
ESAA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myotoxicity 294018 0
Snake envenoming 294116 0
neurotoxicity 298014 0
major bleeding 298015 0
renal impairment 298016 0
Condition category
Condition code
Musculoskeletal 294318 294318 0 0
Other muscular and skeletal disorders
Injuries and Accidents 294431 294431 0 0
Poisoning

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
a)tiger snake and brown snake antivenom
b)1 vial of tiger snake antivenom (3000 units), 1 vial of brown snake antivenom (1000 units)
c) Administered once
d) Intravenous administration
e)Administration of snake antivenom will be as soon as patient presents to hospital and consents to participation
Intervention code [1] 291027 0
Treatment: Drugs
Comparator / control treatment
Standard clinical care for snake bite patients.
Standard clinical practice for any snake bite requires laboratory testing to determine if a patient has been envenomed. The adminstration of antivenom is then based on the presence of clinical effects of envenoming and abnormal laboratory investigations.
Control group
Active

Outcomes
Primary outcome [1] 294119 0
Proportion of patients with significant envenomation defined as the development of one or more of the following effects (composite outcome): i) Myotoxicity defined as a peak CK greater than 1000U/L and local or systemic myalgia ii) Neurotoxicity: paralysis of 2 or more muscle groups (extra-ocular + bulbar) or respiratory paralysis iii) Major bleeding: defined by the International Society on Thrombosis and Haemostasis as fatal bleeding, symptomatic bleeding in a critical organ (e.g. intracranial haemorrhage) or bleeding resulting in a drop of haemoglobin >20g/L or requiring blood transfusion iv) Acute kidney failure injury: defined by the RIFLE criteria (creatinine increasing by 2x or more; <0.5ml/kg/hr urine output over 12h)
Timepoint [1] 294119 0
within 6 hours of snake bite.
Secondary outcome [1] 312542 0
Time to recovery of the (International Normalised Ratio) INR to less than 2
Timepoint [1] 312542 0
Within 24 hours of snake bite
Secondary outcome [2] 312834 0
Early systemic hypersensitivity reactions graded as 1) skin only reaction i.e. generalised itch, erythema, uticaria or angloedema 2)Anaphlaxis: any of No 1 skin reactions and at least one reaction from either respiratory (wheeze, throat tightness, hypoxemia) or cardiovascular systems (new onset of absolute hypotension SBP<90mmHg) 3)Severe Anaphylaxis: Severe if hypotension or hypoxia was observed during above reactions.
Reactions assessed thorugh clinical observation by attending physician.
Timepoint [2] 312834 0
Within 24 hours of snake bite
Secondary outcome [3] 312835 0
Time from randomisation to hospital discharge (hours)
Timepoint [3] 312835 0
At hospital discharge
Secondary outcome [4] 312836 0
Death ocurring prior to hospital disharge
Timepoint [4] 312836 0
At hospital discarge
Secondary outcome [5] 321823 0
Proportion with myotoxicity. Myotoxicity is assessed through symptoms and blood test results.
Timepoint [5] 321823 0
Within 24 hours of snake bite.
Secondary outcome [6] 321824 0
Proportion with neurotoxicity. Assessed by: paralysis of 2 or more muscle groups (extra-ocular + bulbar) or respiratory paralysis.
Timepoint [6] 321824 0
Within 24 hours of snake bite.
Secondary outcome [7] 321825 0
Proportion with major bleeding. Assessed by: defined by the International Society on Thrombosis and Haemostasis as fatal bleeding, symptomatic bleeding in a critical organ (e.g. intracranial haemorrhage) or bleeding resulting in a drop in haemoglobin >20g/L or requiring blood transfusion.
Timepoint [7] 321825 0
Within 24 hours of snake bite.
Secondary outcome [8] 321826 0
Proportion with acute kidney injury. Assessed by: the RIFLE criteria (creatinine increasing by 2x or more; <0.5ml/kg/hr urine output over 12h).
Timepoint [8] 321826 0
Within 24 hours of snake bite.

Eligibility
Key inclusion criteria
1. Presents to hospital within 2 hours of snakebite
2. Definite sighting of a snake by the patient (or parent/carer of child, age >2years) and a confirmed bite.
3. Early non-specific systemic symptoms suggesting envenoming: EITHER: collapse OR two of vomiting, headache, diarrhoea or abdominal pain.
Minimum age
2 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Aged under 2 years of age
2. Definite bite by a non-venomous snake
3. Definite bite by a red-bellied black snake at hospitals where a separate study is being undertaken (Hunter Area Health Hospitals, Manning Base Hospital, Coffs Harbour Hospital, Liverpool Hospital, Campbelltown Hospital)
4. Suspected taipan bites (in northern regions of Australia where taipans occur)
5. Cases consistent with mulga snake envenoming
6. Cases consistent with death adder envenoming
7. Cardiac Arrest.

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)
Enrolment will require contacting the 1800 phone number diverted to one of the chief investigators or research data manager. Brief demographic and clinical data will be faxed, and after informed consent is confirmed, the randomisation will be done by a secure online website. The website will randomly assign each recruit to early snake antivenom or to standard care for snake bite patients
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by online secure webite.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample size will be based on up to 30% of patients with brown snake and tiger snake envenoming developing neurotoxicity, myotoxicity, major haemorrhage or acute kidney injury based on data from ASP and the intention to reduce this to at least 10% of cases. In order to detect whether antivenom decreases the proportion of patients with major envenoming from 30% to 10%, with a significance level (alpha) of 5% and a power of 80%, a minimum of 72 patients must be recruited to each arm of the trial (ie. a total of 144 patients). We will aim to recruit 150 potentially envenomed patients over a 3 year period of recruitment. From 2006 to 2014 ASP has recruited a median of 50 envenomed patients per year presenting to hospital within 2h of the bite. In the process of recruiting these 150 patients potentially 50 to 100 non-envenomed patients will be recruited to the study and receive antivenom.
Statistical analysis will be performed on all envenomed patients with detected venom in their blood. The dichotomous primary outcome will be analysed by intention to treat using Fisher’s exact test comparing those administered early antivenom with those not. Appropriate statistical tests will be used for continuous outcomes depending on whether the data is parametric or non-parametric.
There will be pre-defined subgroup analyses by snake type (determined by venom specific enzyme immunoassay) and by individual major clinical envenoming syndromes (neurotoxicity, myotoxicity, major bleeding and acute kidney injury).

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/09/2016
Actual
26/10/2015
Date of last participant enrolment
Anticipated
1/09/2020
Actual
26/10/2015
Date of last data collection
Anticipated
Actual
28/10/2015
Sample size
Target
150
Accrual to date
Final
1
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 3361 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [2] 5438 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 5439 0
Royal Hobart Hospital - Hobart
Recruitment hospital [4] 5440 0
North West Regional Hospital - Burnie
Recruitment hospital [5] 5441 0
Mersey Community Hospital - Latrobe
Recruitment hospital [6] 5442 0
Launceston General Hospital - Launceston
Recruitment hospital [7] 5443 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 5444 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [9] 5445 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 9144 0
2298 - Waratah West
Recruitment postcode(s) [2] 12923 0
2145 - Westmead
Recruitment postcode(s) [3] 12924 0
7000 - Hobart
Recruitment postcode(s) [4] 12925 0
7320 - Upper Burnie
Recruitment postcode(s) [5] 12926 0
7307 - Latrobe
Recruitment postcode(s) [6] 12927 0
7250 - Launceston
Recruitment postcode(s) [7] 12928 0
4102 - Woolloongabba
Recruitment postcode(s) [8] 12929 0
4101 - South Brisbane
Recruitment postcode(s) [9] 12930 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 293128 0
University
Name [1] 293128 0
The University of Newcastle
Country [1] 293128 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
University Drive, Callaghan
NSW 2308, Australia
Country
Australia
Secondary sponsor category [1] 289321 0
None
Name [1] 289321 0
Address [1] 289321 0
Country [1] 289321 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292260 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 292260 0
Research Ethics and Governance Unit
Hunter New England Local Health District
Locked Bag 1
New Lambton NSW 2305
Ethics committee country [1] 292260 0
Australia
Date submitted for ethics approval [1] 292260 0
30/01/2015
Approval date [1] 292260 0
24/03/2015
Ethics approval number [1] 292260 0
15/02/18/3.03
Ethics committee name [2] 294622 0
Children's Health Queensland Hospital and Health Service Research Governance
Ethics committee address [2] 294622 0
CHQ Research Directorate
Level 7, Centre for Children's Health Research
Lady Cilento Children's Hospital,
62 Graham Street, South Brisbane QLD 4101.
Ethics committee country [2] 294622 0
Australia
Date submitted for ethics approval [2] 294622 0
Approval date [2] 294622 0
16/10/2015
Ethics approval number [2] 294622 0
SSA/15/QRCH/176
Ethics committee name [3] 294623 0
Centres for Health Research Princess Alexandra Hospital, Metro South Hospital and Health Service
Ethics committee address [3] 294623 0
37 Kent Street, Woolloongabba QLD 4102
Ethics committee country [3] 294623 0
Australia
Date submitted for ethics approval [3] 294623 0
Approval date [3] 294623 0
14/09/2015
Ethics approval number [3] 294623 0
SSA/15/QPAH/593
Ethics committee name [4] 294624 0
The Sydney Children's Hospital Network
Ethics committee address [4] 294624 0
Corner Hawkesbury Road
and Hainsworth Street
Locked Bag 4001
Westmead NSW 2145
Sydney Australia
DX 8213 Parramatta
Ethics committee country [4] 294624 0
Australia
Date submitted for ethics approval [4] 294624 0
Approval date [4] 294624 0
14/10/2015
Ethics approval number [4] 294624 0
SSA/15/SCHN/407
Ethics committee name [5] 294625 0
Human Research Ethics Committee Tasmania Network
Ethics committee address [5] 294625 0
Office of Research Services, University of Tasmania, Private Bag 1, Hobart Tasmania 7001.
Ethics committee country [5] 294625 0
Australia
Date submitted for ethics approval [5] 294625 0
Approval date [5] 294625 0
26/10/2015
Ethics approval number [5] 294625 0
H0015315
Ethics committee name [6] 294626 0
Austin Health
Ethics committee address [6] 294626 0
Office for Research, Austin Health
Level 8 HSB, Heidelberg VIC 3084
Ethics committee country [6] 294626 0
Australia
Date submitted for ethics approval [6] 294626 0
03/09/2015
Approval date [6] 294626 0
21/01/2016
Ethics approval number [6] 294626 0
SSA/15/Austin/383

Summary
Brief summary
Currently, standard practice for any snake bite requires laboratory testing to determine if a patient has been envenomed, and coagulation studies are the most important tests. The administration of antivenom is then based on the presence of clinical effects of envenoming and abnormal laboratory investigations. However, many of these envenoming effects are irreversible, so once they develop they are unlikely to be reversed by antivenom. In this case, antivenom needs to be given prior to the development of abnormal laboratory test or clinical effects. The aim of this project will be to administer antivenom early – as soon as the patient presents to hospital, without first waiting for laboratory tests or the development of clinical signs of envenoming, and/or retrieval to a major hospital. The objective is to prevent envenoming effects that may lead to significant morbidity or death.
Trial website
http://www.newcastle.edu.au/research-and-innovation/centre/health-medicine/clinical-toxicology
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 54370 0
Prof Geoffrey Isbister
Address 54370 0
Clinical Toxicology Research Group,
The University of Newcastle, Level 5 New Med Building
Calvary Mater Newcastle, Edith Street Waratah NSW 2298.
Country 54370 0
Australia
Phone 54370 0
+61240144931
Fax 54370 0
+61 2 40143873
Email 54370 0
[email protected]
Contact person for public queries
Name 54371 0
Mrs Jennifer Robinson
Address 54371 0
Clinical Toxicology Research Group,
The University of Newcastle, Level 5 New Med Building
Calvary Mater Newcastle, Edith Street Waratah NSW 2298.
Country 54371 0
Australia
Phone 54371 0
+61240143874
Fax 54371 0
+61 2 40143873
Email 54371 0
[email protected]
Contact person for scientific queries
Name 54372 0
Prof Geoffrey Isbister
Address 54372 0
Clinical Toxicology Research Group,
The University of Newcastle, Level 5 New Med Building
Calvary Mater Newcastle, Edith Street Waratah NSW 2298.
Country 54372 0
Australia
Phone 54372 0
+61240144931
Fax 54372 0
+61 2 40143873
Email 54372 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
There was only one participant in this study, therefore their IPD is unlikely to be useful.


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.