Journal Article

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

Oo, Min Zaw, Ashley, Elizabeth A., Watson, James A., Holmes, Jane, Thwin, Khin Thida, Aung, Zaw Lynn, Warrell, David A., Lamb, Thomas, Nwe, Myat Thet, Smithuis, Frank

2020

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive Clinical Trials as Topic / Anaphylaxis / Anaphylaxis - chemically induced / Animals / Antivenins - administration & dosage / Antivenins - adverse effects / Antivenins - therapeutic use / Antivenom / Bayes Theorem / Bayesian analysis / Biology and Life Sciences / Blood Coagulation - drug effects / Clinical trials / Clinical Trials, Phase II as Topic - methods / Computer Simulation / Daboia - metabolism / Design / Design optimization / Distribution / Dosage / Dose-Response Relationship, Drug / Hemodynamics / Humans / Mathematical models / Medicine and Health Sciences / Models, Statistical / Myanmar / Patient safety / People and Places / Pharmacodynamics / Pharmacokinetics / Pharmacology / Probability theory / Properties / Research and Analysis Methods / Snake Bites - therapy / Toxicity / Tropical diseases / Venom / Viper Venoms - antagonists & inhibitors