Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12609000063213
Ethics application status
Approved
Date submitted
2/12/2008
Date registered
23/01/2009
Date last updated
15/12/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Redback Spider Antivenom Evaluation II Study (RAVE II Study)
Scientific title
Randomised controlled trial of intravenous antivenom versus placebo in the treatment of pain and systemic effects in redback spider bite
Secondary ID [1] 262281 0
RAVE II Study
Universal Trial Number (UTN)
Trial acronym
RAVE-II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Redback spiderbite 4052 0
Condition category
Condition code
Injuries and Accidents 4260 4260 0 0
Other injuries and accidents
Injuries and Accidents 4261 4261 0 0
Poisoning

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Two vials (500U/vial) of redback spider antivenom (CSL Ltd) given as a single dose intravenously diluted in 200 mL of normal saline over 20 minutes.
Intervention code [1] 3776 0
Treatment: Drugs
Comparator / control treatment
Two vials (0.5mL/vial) of normal saline given as a single dose intravenously diluted in 200 mL of normal saline over 20 minutes.
Control group
Placebo

Outcomes
Primary outcome [1] 5143 0
A clinically significant reduction in severity of pain using the verbal numeric rating scale (VNRS). A clinically significant change in the VNRS will be dependent on the baseline VRNS and defined as a change of 2 or greater for baseline score of 0 to 3, greater than 3 for baseline score of 4 to 6, and 5 or greater for baseline score of 7 to 10. This is based on the definition of Bird and Dickson for visual analogue scales.
Timepoint [1] 5143 0
2 hours after the commencement of the trial medication
Primary outcome [2] 5144 0
Resolution of systemic effects in patients presenting with systemic envenoming. Systemic envenoming is defined as the presence of 3 of the following: nausea, vomiting, headache, lethargy, malaise and abdominal pain. This outcome will be assessed using clinical history and examination.
Timepoint [2] 5144 0
2 hours after the commencement of the trial medication
Secondary outcome [1] 8656 0
Administration of opioid analgesics (oral or parenteral) in the emergency department as documented by health care professionals and then recorded on a study datasheet.
Timepoint [1] 8656 0
2 or more hours after commencing the trial medication
Secondary outcome [2] 8657 0
Administration of further doses of antivenom in the emergency department as documented by health care professionals and then recorded on a study datasheet.
Timepoint [2] 8657 0
While in the emergency department up until the time of discharge.
Secondary outcome [3] 8658 0
Clinically significant change in VNRS based on telephone follow-up
Timepoint [3] 8658 0
24 hours after study enrolment
Secondary outcome [4] 8659 0
Use of analgesics after discharge in addition to regular ibuprofen when the patient is questioned on telephone follow up.
Timepoint [4] 8659 0
After discharge until follow up at 7 to 14 days
Secondary outcome [5] 8660 0
Representation to hospital or local medical practitioner as recorded in the medical chart which will be reviewed by the investigators and by questioning the patient on telephone follow up.
Timepoint [5] 8660 0
Within one week of enrolment to the study.
Secondary outcome [6] 8661 0
Immediate allergic reactions as documented by health care professionals and then recorded on a study datasheet.
Timepoint [6] 8661 0
Within 2 hours of trial medicaiton
Secondary outcome [7] 8662 0
Occurrence of serum sickness diagnosed by the clinical trial investigators
Timepoint [7] 8662 0
Within 6 weeks of being given the trial medication

Eligibility
Key inclusion criteria
1.A definite or likely redback spider bite according to either of the following criteria:
a.The spider causing the bite was clearly identified by the patient or clinician, OR
b.A clinical syndrome consistent with typical redback spider envenoming, that is the sensation of a bite followed by two or more of:
1. increasing pain over the first hour
2. radiating, regional or generalised pain
3. local or regional diaphoresis

AND

2.The treating clinician would normally treat the patient with antivenom, namely either for:
1. moderate envenoming = moderate to severe local pain without systemic envenoming, or;
2. severe envenoming = moderate to severe local pain and systemic features
Minimum age
7 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Patients who have received antivenom for this envenoming prior to enrolment
2.Children aged <8 years because of unreliability of the Verbal Numerical Rating Scale for assessment of pain in this group
3.Presentation to hospital >36 hours after the bite

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 one of the chief investigators or designated study nurses through a single 1800 phone number diverted to the person on call. The on-call investigator/study nurse will keep a list of all treatment packs/kits at each site. Brief demographic and clinical data will be collected, and after informed consent has been confirmed, the treating doctor will be given the treatment KIT number to be used for the patient based on a randomised list of treatment kits. The list will simply have the study number and the treatment site and not the allocation to active or placebo.

Based on logistical problems in RAVE-I and the potential errors made in selecting the correct treatment pack by the treating doctor/nurse, the allocation to each treatment pack will be done based on the pre-randomised list of all blocks for all study sites that will be kept by the chief investigators and on-call research nurses. When a patient is enrolled, the research nurse or investigator will find the appropriate pack of 4 based on the hospital site and whether the patient has only local pain or systemic envenoming. They will then take the next study code from the pack (packs will be used in sequential order) and this number will be given to the treating doctor/nurse to identify the treatment kit to be used. Allocation of each study code/treatment pack to active or placebo will only be known by the pharmacy at Calvary Mater Newcastle.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation will be used with random block-sizes and include stratification between patients with local and systemic envenoming. Each site will have 2 packs each containing 4 treatment kits, one pack of 4 for patients with pain only and the other for systemic envenoming. The use of random block sizes will mean that each pack of 4 may contain a mixture of blocks making it impossible for the treating clinicians to predict the last kit in each pack.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
15/12/2008
Actual
24/01/2009
Date of last participant enrolment
Anticipated
Actual
21/06/2013
Date of last data collection
Anticipated
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1322 0
2300

Funding & Sponsors
Funding source category [1] 4233 0
Government body
Name [1] 4233 0
National Health and Medical Research Council
Country [1] 4233 0
Australia
Primary sponsor type
Hospital
Name
Calvary Mater Newcastle
Address
Edith St
Waratah NSW 2298
Country
Australia
Secondary sponsor category [1] 3808 0
University
Name [1] 3808 0
Menzies School of Health Research
Address [1] 3808 0
Rockland Dr
Tiwi NT 0810
Country [1] 3808 0
Australia
Other collaborator category [1] 499 0
Hospital
Name [1] 499 0
Royal Perth Hospital
Address [1] 499 0
Wellington St
Perth WA 6000
Country [1] 499 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6287 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 6287 0
John Hunter Hospital
Lookout Rd
New Lambton NSW 2310
Ethics committee country [1] 6287 0
Australia
Date submitted for ethics approval [1] 6287 0
30/10/2008
Approval date [1] 6287 0
24/11/2008
Ethics approval number [1] 6287 0
08/11/19/3.04

Summary
Brief summary
Redback spider bites are common in Australia and red back spider envenoming (latrodectism) is the commonest significant envenoming in Australia. Redback spider antivenom (RBS AV) is the most frequently used antivenom in Australia. An estimated 5000 redback spider bites are treated with antivenom each year requiring a median of 2 vials of redback spider antivenom and an emergency department or hospital admission. We estimate this costs between $200,000 and $500,000 annually for antivenom and an equivalent amount in hospital costs. Early adverse reactions occur in approximately 4% of cases (40 to 120 patients annually) causing additional risk to the patient and costs to the health care system. Redback antivenom treatment therefore carries a considerable cost and measureable risk. However, despite the wide use of RBS AV and the clinical impression that it is effective, it has never been tested in a placebo randomized controlled trial. The results from our recent randomised controlled trial of intravenous versus intramuscular administration of redback spider antivenom (RAVE I) raise questions about the effectiveness of the antivenom. It is therefore essential to determine whether RBS AV is effective and justifies the costs and risks associated with its use. We propose to determine the effectiveness of RBS AV in a multicentre randomised placebo-controlled trial.
Trial website
N/A
Trial related presentations / publications
Isbister GK, Brown SG, Miller M, Tankel A, MacDonald E, Stokes B et al. A randomised controlled trial of intramuscular vs. intravenous antivenom for latrodectism--the RAVE study. QJM. 2008;101(7):557-65
Public notes

Contacts
Principal investigator
Name 29186 0
A/Prof Geoffrey Isbister
Address 29186 0
Calvary Mater Newcastle
Waratah NSW 2298
Country 29186 0
Australia
Phone 29186 0
+61438446471
Fax 29186 0
Email 29186 0
[email protected]
Contact person for public queries
Name 12343 0
A/Prof Geoff Isbister
Address 12343 0
Calvary Mater Newcastle
Edith St
Waratah NSW 2298
Country 12343 0
Australia
Phone 12343 0
+61 2 49211211
Fax 12343 0
Email 12343 0
[email protected]
Contact person for scientific queries
Name 3271 0
A/Prof Geoff Isbister
Address 3271 0
Calvary Mater Newcastle
Edith St
Waratah NSW 2298
Country 3271 0
Australia
Phone 3271 0
+61 2 49211211
Fax 3271 0
Email 3271 0
[email protected]

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
Dimensions AIRandomized Controlled Trial of Intravenous Antivenom Versus Placebo for Latrodectism: The Second Redback Antivenom Evaluation (RAVE-II) Study2014https://doi.org/10.1016/j.annemergmed.2014.06.006
N.B. These documents automatically identified may not have been verified by the study sponsor.