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.
Did you find this useful? Give us your feedback
Citations
References
7 citations
"A Bayesian phase 2 model based adap..." refers background or methods in this paper
...A dose-finding trial in Daboia siamensis envenoming, Myanmar The primary objective of our proposed study is to determine the optimal initial dose of the novel BPI lyophilised viper antivenom....
[...]
...Following a recent 4-year collaborative initiative between institutions in Myanmar and Australia entitled the Myanmar Snakebite project, antivenom production facilities have improved resulting in the production of a new monospecific lyophilised F(ab)’2 antivenom (Viper antivenom BPI) [11]....
[...]
...This scenario corresponds to the situation whereby the manufacturing of the antivenom is not as good as reported (the reported low toxicity of the novel BPI antivenom in Myanmar is from anecdotal evidence only) and causes frequent (approximately 10% occurrence) toxicity at the starting dose in the adaptive arm....
[...]
...entitled the Myanmar Snakebite project, antivenom production facilities have improved 18 resulting in the production of a new monospecific lyophilised F(ab)’2 antivenom (Viper 19 antivenom BPI) [11]....
[...]
...Aside from the initial dosing of antivenom, 97 patients in each group will be managed according to Myanmar national guidelines [11]....
[...]
6 citations
"A Bayesian phase 2 model based adap..." refers methods in this paper
...We simulated the stochastic behaviour of 367 the trial designs when (i) toxicity is not dose dependent (as argued by [33]) and (ii) 368 when the distribution of venom mass is considerably different from a normal 369 approximation....
[...]
6 citations