Dose of antivenom for the treatment of snakebite with neurotoxic envenoming: Evidence from a randomised controlled trial in Nepal

Abstract

BackgroundCurrently, there is inadequate evidence on which to base clinical management of neurotoxic snakebite envenoming, especially in the choice of initial antivenom dosage. This randomised controlled trial compared the effectiveness and safety of high versus low initial antivenom dosage in victims of neurotoxic envenoming.Methodology/ Principal findingsThis was a balanced, randomised, double-blind trial that was conducted in three health care centers located in the Terai plains of Nepal. Participants received either low (two vials) or high (10 vials) initial dosage of Indian polyvalent antivenom. The primary composite outcome consisted of death, the need for assisted ventilation and worsening/recurrence of neurotoxicity. Hourly evaluations followed antivenom treatment. Between April 2011 and October 2012, 157 snakebite victims were enrolled, of which 154 were analysed (76 in the low and 78 in the high initial dose group). Sixty-seven (43·5%) participants met the primary outcome definition. The proportions were similar in the low (37 or 48.7%) vs. high (30 or 38.5%) initial dose group (difference = 10·2%, 95%CI [-6·7 to 27·1], p = 0·264). The mean number of vials used was similar between treatment groups. Overall, patients bitten by kraits did worse than those bitten by cobras. The occurrence of treatment-related adverse events did not differ among treatment groups. A total of 19 serious adverse events occurred, including seven attributed to antivenom.ConclusionsThis first robust trial investigating antivenom dosage for neurotoxic snakebite envenoming shows that the antivenom currently used in Nepal performs poorly. Although the high initial dose regimen is not more effective than the low initial dose, it offers the practical advantage of being a single dose, while not incurring higher consumption or enhanced risk of adverse reaction. The development of new and more effective antivenoms that better target the species responsible for bites in the region will help improve future patients’ outcomes.Trial registrationThe study was registered on clinicaltrials.gov (NCT01284855) (GJ 5/1)

The timing is right to end snakebite deaths in South Asia

“… 10 11 12 22 Studies on preclinical efficacy, pharmacokinetics, clinical effectiveness, and safety of current antivenoms are lacking. 37 39 56 61 The optimal dose of antivenom is still debated and regional clinical trials offer conflicting evidence. A systematic review of 10 open label randomised controlled trials in the Indian subcontinent on optimal antivenom dose concluded that there is very low quality evidence to guide practice and further research is needed.…”

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: application to a dose-finding trial for a novel Russell’s viper antivenom in Myanmar

“…The objective clinical endpoint used by Alirol et al in neurotoxic envenoming could be adapted as an efficacy endpoint in an adaptive design, i.e. the avoidance of ventilation from a starting position of pre-defined neurological impairment [25]. These simulation studies for both the model based and rule based designs highlight the need for larger phase 2 type dose-finding trials.…”

“…those occurring in 5% or fewer patients). In the dose-finding trials displayed in Supplementary Table S1, six studies demonstrate a trend suggestive of a dose-toxicity relationship [24, 25, 38–41], two studies show the opposite relationship [42, 43] and the remaining eight studies do not report toxicity as an outcome. An earlier study by Reid with large numbers of patients was suggestive of a dose-toxicity relationship [44].…”

“…The particularities of the design reported here were tailor-made for a dose-finding trial in Daboia siamensis envenoming but the design generalises to any systemic envenoming with clinically relevant endpoints whereby the efficacy and toxicity outcomes are both binary, e.g. [13, 24, 25]. We compare the in silico performance of this design against that of a tailor-made rule based design (modified ‘3+3’ design) under multiple simulation scenarios.…”

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: Application to a dose-finding trial for a novel Russell’s viper antivenom in Myanmar

“…The objective clinical endpoint used by Alirol et al in neurotoxic envenoming could be adapted as an efficacy endpoint in an adaptive design, i.e. improvement in FEV1 or the avoidance of ventilation from a starting position of pre-defined neurological impairment [27]. These simulation studies for both the model based and rule based designs highlight the need for larger phase 2 type dose-finding trials.…”