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
Summary (2 min read)
Introduction
- Snake-bite envenoming (SBE) was re-categorized as a priority neglected tropical disease by the World Health Organization (WHO) in 2017 [1, 2].
- Many antivenoms will have narrow therapeutic windows and cannot be ethically administered to healthy volunteers, therefore dose optimisation trials need to simultaneously assess efficacy and toxicity.
- Rule based designs do not use information accrued across dosing levels, and therefore they have limited ability to rapidly identify the desired optimal dose with high confidence [15].
Methods
- In this section the authors give an overview of how doses are adaptively chosen during the trial and describe the necessary parameters for the adaptive assignment of doses to patients sequentially enrolled.
- During this burn-in period, patients randomised to the adaptive arm are given the starting dose for the adaptive arm, which is the optimal dose under the prior distribution over the model parameters.
- This is equivalent to fitting a Bayesian logistic regression model to the toxicity outcomes.
Simulation study
- The authors compared the stochastic behaviours of the model based and the rule based designs using a simulation study.
- The authors simulated 2000 independent trials under seven scenarios, whereby each scenario specifies a simulation truth MTD and TED and underlying dose-toxicity and dose-efficacy relationships.
- By ‘toxic- ity driven’, the authors mean that the MTD is strictly less than the TED.
- The optimal dose is ‘efficacy driven’ and lower than their prior estimate (120 mL).
- The following keywords “antiven�” and “dosefinding” or “clinical trial” were used and searched for on the first of November 2019.
Results
- Literature review on antivenom dose-finding trials Using the search criteria, 112 abstracts were reviewed for suitability.
- Four papers performed a retrospective review of antivenom doses and 10 studies were conducted/plan to be conducted prospectively.
- Simulation study comparing rule based and model based designs.
- At the 260th patient, 91% of the simulated trials under the model based design assign a dose within ±10% of the optimal dose.
Discussion
- Antivenoms for the management of SBE have been subjected to few of the sequential clinical studies required of new therapeutics for other diseases, both prior to and post licensing.
- The unknown rate of toxicity and possibly narrow therapeutic window further underlines the need for well designed dose-finding trials with well defined efficacy and toxicity endpoints.
- As described earlier, clinical trials in antivenom therapy rarely define clear toxicity endpoints and are not powered to accurately characterise rare events (i.e. those occurring in 5% or fewer patients).
- Limitations of the Bayesian model based adaptive design Despite these limitations, the authors believe that this Bayesian model based design is particularly pertinent to assessing the optimal dose of BPI Viper Antivenom for Daboia siamensis envenoming in Myanmar.
Author Contributions
- James A. Watson, Thomas Lamb, Jane Holmes, David A. Warrell, Frank Smithuis, Elizabeth A. Ashley, also known as Conceptualization.
- James A. Watson, Elizabeth A. Ashley, also known as Project administration.
- Jane Holmes, David A. Warrell, Elizabeth A. Ashley, also known as Supervision.
- Writing – review & editing: James A. Watson, Thomas Lamb, Jane Holmes, David A. Warrell, Khin Thida Thwin, Zaw Lynn Aung, Min Zaw Oo, Myat Thet Nwe, Frank Smithuis, Elizabeth A. Ashley.
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References
1,572 citations
"A Bayesian phase 2 model based adap..." refers methods in this paper
...The primary outcome used for determining toxicity of the initial dose 128 is the occurrence of an anaphylactic reaction within 180 minutes of antivenom 129 administration, as described by Sampson et al and accepted by the European Academy 130 of Allergy and Clinical Immunology [28]....
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...The primary outcome used for determining toxicity of the initial dose is the occurrence of an anaphylactic reaction within 180 minutes of antivenom administration, as described by Sampson et al and accepted by the European Academy of Allergy and Clinical Immunology [28]....
[...]
1,469 citations
"A Bayesian phase 2 model based adap..." refers background in this paper
...per year [3, 4], the burden of which disproportionately affects the poorest 5 communities [5, 6]....
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1,402 citations
"A Bayesian phase 2 model based adap..." refers methods in this paper
...The original rule based designs [16] and model based 56 designs [19] for dose-finding were published around the same time....
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...The continual reassessment method [19] 52 was the first proposed model based design for dose-finding....
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816 citations
"A Bayesian phase 2 model based adap..." refers background or methods in this paper
...The original rule based designs [16] and model based 56 designs [19] for dose-finding were published around the same time....
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...The ‘3+3’ design is the best known rule based adaptive 43 design [16]....
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761 citations
"A Bayesian phase 2 model based adap..." refers background or methods in this paper
...The superior operating characteristics and greater efficiency 392 are well described in the literature [20]....
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...Although model 57 based designs are more efficient, more flexible and have better operating 58 characteristics [20], rule-based designs have been the dominant choice....
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