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

Abstract

For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined ‘optimal dose’. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell’s viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified ‘3+3’ design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.

Access to antivenoms in the developing world: A multidisciplinary analysis

“…Independent analysis has shown that manufacturers’ dose recommendations are often unrealistic, and lack of published supporting data reinforces this view ( Calvete et al, 2016 ; Harrison et al, 2017 ). Antivenoms should not be given registration or marketing authorization by national regulatory authorities in the absence of independent preclinical neutralization tests and well-designed, pragmatic clinical dose-finding and safety studies ( Williams et al, 2018 ; Watson, 2020 ). For healthcare providers and drug regulatory agencies to be able to determine the effective clinical dose of a given product, the amount of venom that is completely neutralized by a milliliter of antivenom should be indicated.…”

Managing snakebite

“…Robust clinical data on the safe and effective initial dose of antivenom are lacking for most products. 102 Clinicians often rely on manufacturers’ recommendations provided as package inserts or labels, but these can be unreliable. 103 104 We suggest following national protocols or standard regional guidelines for dose.…”

“…The risks of anaphylaxis and sensitisation to animal proteins in antivenoms place ethical limitations on conventional phase I/II designs. 124 Some literature suggests that model based adaptive designs, as used to test anticancer drugs, could be safer alternatives for antivenom testing 95 102 124 …”

Clinical management of snakebite envenoming: Future perspectives

“…The method has, however, been criticized ( Chippaux and Boyer, 2010 ), and modifications entailing commencement with a higher dose followed by subsequent de-escalation have been suggested, especially following presynaptic neurotoxic envenomings, where clinical manifestations may be irreversible and should be timely prevented. Recently, a Bayesian model-based adaptive design has been suggested to be more efficient and has the capacity to enroll larger patient sample sizes determined by simulations ( Watson et al, 2020 ). This is also more flexible and has better operating characteristics than the CRM.…”

“…Both approaches are suitable for safety and efficacy assessments with binary outcomes. The adaptive design was developed to be used to determine the optimal safe and effective dose of a new antivenom used to treat Russell's viper envenoming in Myanmar and will probably be increasingly used to introduce antivenoms into clinical management ( Watson et al, 2020 ).…”