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

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.