Comparison of Two Dose Regimens of Snake Antivenom for the Treatment of Snake Bites Envenoming in Nepal

Study Overview
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Brief Summary
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This study aims at comparing two doses of antivenom in the treatment of snake bite envenoming. It will take place in 3 centers in rural Nepal and will involve 250 snake bite victims presenting with one or more sign of neurotoxic envenoming. The objective of the study is to generate enough scientific evidence to improve Nepal's current national guidelines for the management of snake bites.

Detailed Description
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Snake bites are considered as one of the major neglected public health issues of tropical areas. They occur chiefly in developing countries and mainly affect poor rural communities. Besides the inadequate supply, distribution and accessibility of antivenom, a major problem is the absence of standardized and adequate treatment protocol. There is a significant diversity in clinical practices, in particular concerning the dose of antivenom given. Additionally, antivenom is often given even in the absence of a clear indication for envenoming. Altogether, this leads to an incredible waste of a scarce and costly resource. In Nepal there are gross disparities in the management and outcomes of snake bite envenoming. The country's national guidelines, issued in 2004, prescribe an initial antivenom dose that is 5 times less than the one advocated by most experts. The dosage recommended by the National guidelines is not based on scientific or clinical evidence, and currently, there is confusion about the adequate dose to be administered. Some physicians follow recommendations published by experts, others follow the National guidelines, but for most, dosage is arbitrary. These discrepancies directly impact on morbidity and mortality and lead to wastage of a costly treatment that few can afford. The principal objective of the study is to establish unequivocally which dosage regimen is the most appropriate for the treatment of snake bite neurotoxic envenoming. It is a randomized, double-blind, clinical trial comparing high and low initial doses of snake polyvalent antivenom also known as Anti Snake Venom Serum (ASVS). 250 snake bite victims showing signs of neurotoxic envenoming will be enrolled over 2 years in three health centres of Southern Nepal. Each participant will initially receive either 2 vials or 10 vials of snake polyvalent antivenom. Mortality, the proportion of patients needing assisted respiration, and the percentage of patients who show worsening of neurotoxic signs and therefore require additional doses of antivenom will be compared in both arms. The kinetics of recovery and the total consumption of antivenom will also be compared. Finally, the incidence and severity of early and late adverse reactions to antivenom will be assessed. The economical impact of snake bite envenoming will also be determined by measuring direct and indirect costs to both health services and individual victims. Because they chiefly affect agricultural workers and children, snake bites have serious economic consequences, a fact that is frequently overlooked by national authorities.

Official Title
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A Randomized, Double-blind, Clinical Trial of Two Dose Regimens of VINS Polyvalent Antivenom (ATC J06AA03) for the Treatment of Snake Bites With Neurotoxic Envenoming in Nepal

Conditions
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Snake Bite

Intervention / Treatment
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* Drug: Antivenom


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of snake bite; AND Age ≥ 5 years; AND Informed consent obtained; AND Showing one or more signs of neurotoxic envenoming Exclusion Criteria: Subject unlikely to co-operate in the study Pregnant or breastfeeding women Patients presenting more than 24 hours after the bite Patients requiring ventilation support at the time of presentation Subjects with previous history of snake bite with envenoming Patients who already received antivenom before presenting to the study centre Patients with pre-existing neurological or muscular disorders Subjects with known history of allergy to horse proteins Patients with proven viper bites

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low initial dose<br>This arms corresponds to Nepal national protocol and involves the initial administration of 2 vials of antivenom over one hour followed by the slow infusion of 4 vials over 4 hours | Drug: Antivenom<br>* Polyvalent antivenom directed against Indian spectacled cobra (N. naja), common Indian krait (B. caeruleus), saw-scaled viper (Echis carinatus) and Russell's viper.<br>* Other names: VINS Bioproduct;|
| Experimental: High initial dose<br>This arms corresponds to Indian national protocol and involves the initial administration of 10 vials of antivenom over one hour followed by the slow infusion of saline over 4 hours | Drug: Antivenom<br>* Polyvalent antivenom directed against Indian spectacled cobra (N. naja), common Indian krait (B. caeruleus), saw-scaled viper (Echis carinatus) and Russell's viper.<br>* Other names: VINS Bioproduct;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint: Number of patients who either 1) died, or 2) needed assisted ventilation, or 3) showed a worsening of envenoming signs during hospital stay | The endpoint is composite and includes the number of patients who die during hospitalization are put under assisted ventilation during hospitalization necessitate additional doses of antivenom because of a worsening of neurotoxicity. A worsening of neurotoxicity will be defined as the appearance of 2 new neurotoxic signs OR the appearance of a severe neurotoxic sign (i.e. loss of gag reflex or paradoxical breathing) | Participants will be followed for the duration of hospital stay, an expected average of 5 days | 
| Number of patients with a Serious Adverse Events |  | Last follow-up visit (6 months after randomization) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Number of deaths | Participants will be followed for the duration of hospital stay, an expected average of 5 days | 
| Total amount of antivenom administered |  | Participants will be followed for the duration of hospital stay, an expected average of 5 days | 
| Time to recovery | Time between admission to the health centre and the disappearance of all neurotoxic sign s | Participants will be followed for the duration of hospital stay, an expected average of 5 days | 
| Total cost of treatment | Including direct (antivenom and other drugs costs, costs of hospitalization, and costs of Adverse Events management)and indirect costs (working days missed) | Last follow-up visit (6 months after randomization) | 
| Number of patients with Adverse Events |  | Last follow-up visit (6 months after randomization) | 
| Number of patients who needed assisted ventilation during hospitalization |  | Participants will be followed for the duration of hospital stay, an expected average of 5 days | 
| Number of patients who showed a worsening of neurotoxicity during hospitalization |  | Participants will be followed for the duration of hospital stay, an expected average of 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurotoxic envenoming (WHO ICD-10 T63.0)