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Trial registered on ANZCTR


Registration number
ACTRN12612001062819
Ethics application status
Approved
Date submitted
28/09/2012
Date registered
4/10/2012
Date last updated
25/06/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I/Phase II randomized controlled trial (RCT) of a new antivenom, compared to the currently used CSL taipan antivenom, for the treatment of the effects of Papuan taipan bite
Scientific title
A randomized controlled trial (RCT) of a new monovalent antivenom (ICP Papuan taipan antivenom) for the treatment of Papuan taipan (Oxyuranus scutellatus) envenoming in Papua New Guinea to measure safety, minimum dose and effectiveness in the prevention of neurotoxic paralysis, arrest of coagulopathy and other effects of envenoming.
Secondary ID [1] 281344 0
Nil known
Universal Trial Number (UTN)
U1111-1135-2082
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Papuan taipan (Oxyuranus scutellatus) envenoming 285669 0
Condition category
Condition code
Injuries and Accidents 285852 285852 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The research aims to establish the safety, minimum dose and clinical effectiveness of two antivenoms in the treatment of envenoming by Papuan taipan snakes (Oxyuranus scutellatus):

1. ICP monovalent Papuan taipan antivenom, manufactured by the Instituto Clodomiro Picado at the Universidad de Costa Rica in San Jose, Costa Rica;
2. CSL monovalent taipan antivenom, manufactured by CSL Limited, in Parkville, Victoria, Australia.

Both antivenoms will be administered as an initial dose of 1 vial containing a minimum of 12,000 units of neutralising immunoglobulins. Decisions about repeat doses will be made after patient review at 6 hours. Typically a repeat dose will only be given if the patient still has an abnormal clotting profile IN COMBINATION with active abnormal bleeding.

Both products are formulated to contain at least 12,000 Units of neutralising immunoglobulins (per vial) specific to venom from taipan snakes (Oxyuranus scutellatus) from Papua New Guinea (ICP antivenom) or Australia (CSL antivenom), and will be subjected to (i) a Phase I dose-finding and safety study using a modified '3+3' design in descending doses, involving up to 18 patients, and (ii) a Phase II double-blinded, randomised controlled study involving up to 370 patients divided equally between two arms. Patients with a diagnosis of Papuan taipan envenoming who present to the Emergency Department at the Port Moresby General Hospital, and who meet inclusion criteria will be invited to participate in the study. After obtained informed consent they will randomised into one of two treatment groups in equal proportions according to sex and age.

All patients will be treated according to a standard protocol for the management of snakebite with the only difference being that the two Groups will receive different antivenom products, and neither the patients, medical personnel nor the researchers who handle and analyse the data will know which antivenom is being used with either of the Groups. This will be achieved by masking the identities of the antivenom vials, rendering them identifiable only by reference to a list that will be kept locked away in Melbourne until the end of the trial and completion of the analysis.

Patients who are recruited to the trials will receive a thorough examination, combined with a pre-antivenom blood draw for laboratory tests [full blood counts, coagulation profile and clotting factors, muscle enzymes, renal function and electrolytes, liver function, troponin I and quantitative ELISA determination of serum venom levels]. Each patient will receive a single, specified dose of the antivenom allocated to that group. Routine premedication with subcutaneous adrenaline (according to the established protocol within the PMGH Emergency Department) will be administered not more than 10 minutes pre-antivenom. Antivenoms will be administered intravenously, made up to 100 ml with normal saline and given over 30 minutes. Patients will be individually monitored at the bedside by a trial nurse during antivenom administration, and all necessary drugs and equipment for the treatment of adverse drug reactions (ADR) will be prepared and kept at the bedside. Any patient who develops signs of an ADR will have their antivenom infusion suspended immediately, while the ADR is assessed and treated. Antivenom treatment will be resumed once the attending clinician is satisfied that the reaction has adequately resolved. After receiving the first antivenom dose patients will be monitored continuously for a minimum of 24 hours. A standard neurological examination will be carried out hourly to assess patients objectively for the development of signs of worsening paralysis. A repeat 20WBCT will be conducted at six hourly intervals post-antivenom administration and venous blood collected for repeat laboratory investigations. Results of (A) one hourly neurological assessments and (B) bedside clotting tests (20WBCT) every six hours will form the basis for subsequent management decisions, and any additional doses of antivenom will be administered if indicated by the results of these evaluations. Patients who develop airway obstruction or respiratory paralysis post-antivenom will be deemed to have reached the primary endpoint, and will be transferred to the ICU for respiratory support. Patients who develop other complications directly or indirectly related to their envenoming will be seen by other specialist physicians at PMGH as deemed necessary. All patients will be reviewed prior to discharge, and a follow-up appointment will be made for four weeks post-discharge.
Intervention code [1] 284110 0
Treatment: Drugs
Comparator / control treatment
CSL monovalent taipan antivenom, manufactured by CSL Limited, in Parkville, Victoria, Australia will be used as the active control treatment, since this product is the current gold standard immunotherapy intervention for treatment of envenoming by species of snakes belonging to the genus Oxyuranus in Australia, Papua New Guinea and Indonesia's Papua Province. An initial dose of 1 vial, containing a minimum of 12,000 units of neutralising immunoglobulins will be administered. Decisions about repeat doses will be made after patient review at 6 hours. Typically a repeat dose will only be given if the patient still has an abnormal clotting profile IN COMBINATION with active abnormal bleeding.
Control group
Active

Outcomes
Primary outcome [1] 288077 0
Prevention of airway obstruction or respiratory failure (the two most lethal effects of taipan venom) post-antivenom.
Timepoint [1] 288077 0
24 hours post-treatment
Primary outcome [2] 288078 0
Restoration of blood coagulability, as determined by a negative 20 minute whole blood clotting test validated by laboratory findings of normal range PT, APTT and fibrinogen measured on a Diagnostica Stago STA Compact Haemostasis system.
Timepoint [2] 288078 0
48 hours post-treatment
Secondary outcome [1] 299382 0
Length of hospital stay
Timepoint [1] 299382 0
Measured from time of admission to time of discharge

Eligibility
Key inclusion criteria
(i). Only patients who present to the Emergency Department within four (4) hours post-bite;
(ii). Who meet predetermined minimal criteria for the diagnosis of taipan envenoming;
(iii). Give informed consent; and,
(iv). Do not have any of the predetermined exclusion criteria, will be enrolled.
(v). Patients who present more than four (4) hours post-bite, or who have any other exclusion
criteria, will be treated according to the current national protocol.
Minimum age
2 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(i). All patients who present to hospital more than four (4) hours post-bite;
(ii). Any patients with clinical evidence of intracranial haemorrhage;
(iii). Any patient with progressive oropharyngeal paralysis with partial or complete loss of airway
patency, including any patient requiring endotracheal intubation;
(iv). Any patient with significant known co-morbidities (such as active TB, AIDS, diabetes
requiring medication or ischaemic heart disease);
(v). Any patient who has already received treatment with antivenom at another health facility.

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)
Patients will be allocated into treatment groups ‘A’ or ‘B’ using a balanced, stratified randomisation based on age and sex. Patients in each of the four strata will be allocated into either Group ‘A’ or Group ‘B’ in balanced blocks per subgroup, based on computer-generated random number lists used to produce allocation envelopes. Coloured envelopes will be used to indicate each of the
specific strata (e.g.: Male/Adult, Male/Child, Female/Adult, Female/Child). Consenting patients who meet the inclusion criteria will be assigned to a stratum based on sex and age, and the next envelope of the subgroup’s colour retrieved and opened to uncover the treatment group assignment (either Group A or Group B). Both treatment groups will, thus, be randomly allocated equal proportions of male/female and children/adults.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The random number lists and allocation envelopes will be produced by computerised randomisation generation by the trial biostatistician. The treatment group to which a patient is allocated will determine which of the two blinded antivenoms (Group A or Group B) are administered. None of the clinical researchers based in PNG will know which antivenom was assigned to these groups.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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 outside Australia
Country [1] 4074 0
Papua New Guinea
State/province [1] 4074 0
National Capital District
Country [2] 4075 0
Papua New Guinea
State/province [2] 4075 0
Central Province
Country [3] 4076 0
Papua New Guinea
State/province [3] 4076 0
Gulf Province

Funding & Sponsors
Funding source category [1] 286079 0
Government body
Name [1] 286079 0
National Health & Medical Research Council
Address [1] 286079 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 286079 0
Australia
Funding source category [2] 286080 0
Government body
Name [2] 286080 0
Office of Higher Education
Address [2] 286080 0
Level 2, Mutual Rumana
Waigani Drive
Waigani, NCD., 111
Country [2] 286080 0
Papua New Guinea
Primary sponsor type
University
Name
University of Melbourne
Address
Australian Venom Research Unit,
Department of Pharmacology,
Grattan Street,
Parkville, Vic., 3010.
Country
Australia
Secondary sponsor category [1] 284897 0
None
Name [1] 284897 0
Address [1] 284897 0
Country [1] 284897 0
Other collaborator category [1] 277101 0
University
Name [1] 277101 0
University of Papua New Guinea
Address [1] 277101 0
Charles Campbell Toxinology Centre,
School of Medicine & Health Sciences,
Taurama Road,
Boroko, NCD., 112
Country [1] 277101 0
Papua New Guinea
Other collaborator category [2] 277478 0
Hospital
Name [2] 277478 0
Port Moresby General Hospital
Address [2] 277478 0
Taurama Road, Boroko, NCD, 111
Country [2] 277478 0
Papua New Guinea
Other collaborator category [3] 277479 0
Charities/Societies/Foundations
Name [3] 277479 0
Charles Campbell Toxinology Centre
Address [3] 277479 0
Basic Medical Sciences Building, School of Medicine & Health Sciences, University of Papua New Guinea, Taurama Road, Boroko, NCD 111.
Country [3] 277479 0
Papua New Guinea

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288133 0
School of Medicine & Health Sciences Ethics Committee
Ethics committee address [1] 288133 0
Taurama Road Campus,
University of Papua New Guinea
Boroko, 112, NCD,
Ethics committee country [1] 288133 0
Papua New Guinea
Date submitted for ethics approval [1] 288133 0
03/11/2011
Approval date [1] 288133 0
28/11/2011
Ethics approval number [1] 288133 0
N/A
Ethics committee name [2] 288134 0
Medical Research Advisory Committee
Ethics committee address [2] 288134 0
Department of Health,
P.O. Box 807,
Waigani, NCD, 131.
Ethics committee country [2] 288134 0
Papua New Guinea
Date submitted for ethics approval [2] 288134 0
30/11/2011
Approval date [2] 288134 0
05/12/2011
Ethics approval number [2] 288134 0
11.39
Ethics committee name [3] 288135 0
Human Research Ethics Committee
Ethics committee address [3] 288135 0
University of Melbourne,
Level 1, 780 Elizabeth Street,
Parkville, Vic, 3010
Ethics committee country [3] 288135 0
Australia
Date submitted for ethics approval [3] 288135 0
03/10/2012
Approval date [3] 288135 0
22/10/2012
Ethics approval number [3] 288135 0
1238878.1

Summary
Brief summary
We have developed a new, whole IgG, equine, monovalent antivenom for the treatment of Papuan taipan (Oxyuranus scutellatus) envenoming in Papua New Guinea. This product, developed through a collaboration between the School of Medicine & Health Sciences (University of Papua New Guinea), Australian Venom Research Unit (University of Melbourne) and the Instituto Clodomiro Picado (Universidad de Costa Rica), has been subjected to preclinical assessment in accordance with current World Health Organisation (WHO) recommendations for the evaluation of candidate antivenoms, and has been shown to have overall potency against the lethal effects of Papuan taipan venom equivalent to the antivenom currently available in Papua New Guinea (CSL taipan antivenom). Furthermore, the new antivenom has equivalent activity against the myotoxic and phospholipase A2 activity of Papuan taipan venom, but superior potency against the medically important procoagulant effects. We herein propose that following an initial small scale, preliminary dose-finding and safety Phase I study using a blinded, randomised, de-escalating dose “3+3” comparative design (against CSL taipan antivenom), similar to what is used to test potentially dangerous anti-cancer drugs, we will undertake a much more comprehensive, Phase II double-blinded, randomised controlled trial. The aim of this study will be to determine if the new antivenom is non-inferior to the current CSL taipan antivenom when used in the treatment of early envenoming by Papuan taipans. The information obtained from this study will provide data to be used in determining if an application to register the new antivenom in PNG is appropriate.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33677 0
Dr Simon D Jensen
Address 33677 0
Australian Venom Research Unit, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Vic, 3010.
Country 33677 0
Australia
Phone 33677 0
+61 3 8344 7753
Fax 33677 0
Email 33677 0
simondjensen@hotmail.com
Contact person for public queries
Name 16924 0
Mr David Williams
Address 16924 0
Australian Venom Research Unit,
Department of Pharmacology,
University of Melbourne,
Grattan Street,
Parkville, Vic, 3010.
Country 16924 0
Australia
Phone 16924 0
+675 7671 9476
Fax 16924 0
Email 16924 0
david.williams@unimelb.edu.au
Contact person for scientific queries
Name 7852 0
Mr David Williams
Address 7852 0
Australian Venom Research Unit, Department of Pharmacology & Therapeutics, University of Melbourne, Grattan Street, Parkville, Vic, 3010.
Country 7852 0
Australia
Phone 7852 0
+675 7671 9476
Fax 7852 0
Email 7852 0
david.williams@unimelb.edu.au

No information has been provided regarding IPD availability
Summary results
No Results