Snakebite envenoming is a major cause of morbidity and mortality in rural communities throughout the tropics. Generally, the main clinical features of snakebites are local swelling, tissue necrosis, shock, spontaneous systemic hemorrhage, incoagulable blood, paralysis, rhabdomyolysis, and acute kidney injury. These clinical manifestations result from complex biochemical venom constituents comprising of cytotoxins, hemotoxins, neurotoxins, myotoxins, and other substances. Timely diagnosis of envenoming and identification of the responsible snake species is clinically challenging in many parts of the world and necessitates prompt and thorough clinical assessment, which could be supported by the development of reliable, affordable, widely-accessible, point-of-care tests. Conventional antivenoms based on polyclonal antibodies derived from animals remain the mainstay of therapy along with supportive medical and surgical care. However, while antivenoms save countless lives, they are associated with adverse reactions, limited potency, and are relatively inefficacious against presynaptic neurotoxicity and in preventing necrosis. Nevertheless, major scientific and technological advances are facilitating the development of new molecular and immunologic diagnostic tests, as well as a new generation of antivenoms comprising human monoclonal antibodies with broader and more potent neutralization capacity and less immunogenicity. Repurposed pharmaceuticals based on small molecule inhibitors (e.g., marimastat and varespladib) used alone and in combination against enzymatic toxins, such as metalloproteases and phospholipase A2s, have shown promise in animal studies. These orally bioavailable molecules could serve as early interventions in the out-of-hospital setting if confirmed to be safe and efficacious in clinical studies. Antivenom access can be improved by the usage of drones and ensuring constant antivenom supply in remote endemic rural areas. Overall, the improvement of clinical management of snakebite envenoming requires sustained, coordinated, and multifaceted efforts involving basic and applied sciences, new technology, product development, effective clinical training, implementation of existing guidelines and therapeutic approaches, supported by improved supply of existing antivenoms.

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Clinical management of snakebite envenoming: Future perspectives.

Access to safe, effective, quality-assured antivenom products that are tailored to endemic venomous snake species is a crucial component of recent coordinated efforts to reduce the global burden of snakebite envenoming. Multiple access barriers may affect the journey of antivenoms from manufacturers to the bedsides of patients. Our review describes the antivenom ecosystem at different levels and identifies solutions to overcome these challenges. At the global level, there is insufficient manufacturing output to meet clinical needs, notably for antivenoms intended for use in regions with a scarcity of producers. At national level, variable funding and deficient regulation of certain antivenom markets can lead to the procurement of substandard antivenom. This is particularly true when producers fail to seek registration of their products in the countries where they should be used, or where weak assessment frameworks allow registration without local clinical evaluation. Out-of-pocket expenses by snakebite victims are often the main source of financing antivenoms, which results in the underuse or under-dosing of antivenoms, and a preference for low-cost products regardless of efficacy. In resource-constrained rural areas, where the majority of victims are bitten, supply of antivenom in peripheral health facilities is often unreliable. Misconceptions about treatment of snakebite envenoming are common, further reducing demand for antivenom and exacerbating delays in reaching facilities equipped for antivenom use. Multifaceted interventions are needed to improve antivenom access in resource-limited settings. Particular attention should be paid to the comprehensive list of actions proposed within the WHO Strategy for Prevention and Control of Snakebite Envenoming.

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Access to antivenoms in the developing world: A multidisciplinary analysis.

A randomized blinded comparison of two doses of antivenom in the treatment of Bothrops envenoming in São Paulo, Brazil

Who is a tropical doctor

• Bites from venomous snakes can result in bleeding, paralysis, long term disability, and death • Immobilise the bitten limb when transporting the patient to a medical facility; the universal use of pressure immobilisation is controversial, and tourniquets are not recommended • The 20-minute whole blood clotting test is a simple bedside test to screen for and monitor coagulopathy in resource-limited settings • Assess vital parameters and initiate resuscitation measures if the patient is clinically unstable with signs of bleeding, shock, paralysis, or respiratory distress • Intravenous antivenom is recommended in patients with systemic symptoms; the dose and type depend on likely snake species, local guidelines, and availability

Managing snakebite

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.

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

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. less 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 dose9.

Adequate sample sizes for adaptive dose-finding trials can be determined by simulation studies. 
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 Russell9s 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 Russell9s viper 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+39 design). The model based design can identify the optimal dose after fewer patients than the rule based design. Open source code for the simulations can be used to calculate sample sizes under a priori beliefs of efficacy and toxicity. 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.

/pdf/a-bayesian-phase-2-model-based-adaptive-design-to-optimise-2hnfvvl50k.pdf

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

Zaw Lynn Aung

Papers

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

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